View source for Developmental bioelectricity

{{Short description|Electric current produced in living cells}}
{{For|neuroelectric signalling|action potential}}
{{excessive citations|date=November 2023}}
[[File:Bioelectricity Figure 1.png|thumb|upright=2|The morphogenetic field of pattern formation and maintenance during an organism's lifespan<ref>{{cite journal |last=Levin |first=Michael |title=The wisdom of the body: Future techniques and approaches to morphogenetic fields in regenerative medicine, developmental biology and cancer |journal=Regenerative Medicine |year=2011 |volume=6 |issue=6 |pages=667–673 |doi=10.2217/rme.11.69 |pmid=22050517}}</ref>]]
'''Developmental bioelectricity''' is the [[Regulation of gene expression|regulation]] of [[Cell (biology)|cell]], [[Tissue (biology)|tissue]], and organ-level patterning and behavior by electrical signals during the [[developmental biology|development of embryonic animals and plants]]. The charge carrier in developmental bioelectricity is the [[ion]] (a charged atom) rather than the [[electron]], and an electric current and field is generated whenever a net ion flux occurs. Cells and tissues of all types use flows of ions to communicate electrically. Endogenous [[electric current]]s and [[Electric field|fields]], ion fluxes, and differences in resting potential across tissues comprise a signalling system. It functions along with biochemical factors, [[Transcription (biology)|transcriptional]] networks, and other physical forces to regulate cell behaviour and large-scale patterning in processes such as [[embryogenesis]], [[Regeneration (biology)|regeneration]], and [[cancer]] suppression.

== Overview ==

Developmental bioelectricity is a sub-discipline of biology, related to, but distinct from, [[neurophysiology]] and [[bioelectromagnetics]]. Developmental bioelectricity refers to the endogenous ion fluxes, transmembrane and transepithelial voltage gradients, and electric currents and fields produced and sustained in living cells and tissues.<ref>{{cite journal |pmid=25425556 |pmc=4244194 |year=2014 |last1=Levin |first1=M |title=Molecular bioelectricity: How endogenous voltage potentials control cell behavior and instruct pattern regulation in vivo |journal=Molecular Biology of the Cell |volume=25 |issue=24 |pages=3835–3850 |doi=10.1091/mbc.E13-12-0708 }}</ref><ref name=pmid26566112>{{cite journal |doi=10.1146/annurev-cellbio-100814-125338 |pmid=26566112 |title=Ion Channels in Development and Cancer |journal=Annual Review of Cell and Developmental Biology |volume=31 |pages=231–247 |year=2015 |last1=Bates |first1=Emily |doi-access=free }}</ref> This electrical activity is often used during embryogenesis, regeneration, and cancer suppression—it is one layer of the complex field of signals that impinge upon all cells ''in vivo'' and regulate their interactions during pattern formation and maintenance. This is distinct from neural bioelectricity (classically termed electrophysiology), which refers to the rapid and transient spiking in well-recognized excitable cells like [[neuron]]s and [[myocyte]]s (muscle cells);<ref name=pmid24773017>{{cite journal |doi=10.1146/annurev-biophys-051013-022717 |pmid=24773017 |title=Bringing Bioelectricity to Light |journal=Annual Review of Biophysics |volume=43 |pages=211–232 |year=2014 |last1=Cohen |first1=Adam E |last2=Venkatachalam |first2=Veena |doi-access=free }}</ref> and from bioelectromagnetics, which refers to the effects of applied electromagnetic radiation, and endogenous electromagnetics such as [[biophoton]] emission and magnetite.<ref>{{cite journal |pmid=19167986 |year=2009 |last1=Funk |first1=R. H |title=Electromagnetic effects - from cell biology to medicine |journal=Progress in Histochemistry and Cytochemistry |volume=43 |issue=4 |pages=177–264 |last2=Monsees |first2=T |last3=Ozkucur |first3=N |doi=10.1016/j.proghi.2008.07.001 }}</ref><ref>{{cite journal |pmid=16804297 |year=2006 |last1=Funk |first1=R. H |title=Effects of electromagnetic fields on cells: Physiological and therapeutic approaches and molecular mechanisms of interaction. A review |journal=Cells Tissues Organs |volume=182 |issue=2 |pages=59–78 |last2=Monsees |first2=T. K |doi=10.1159/000093061 |s2cid=10705650 |url=http://tud.qucosa.de/id/qucosa%3A27702 }}</ref>

[[File:MinZhaoImage1.jpg|thumb|Membrane potential and transepithelial potential.<ref name=pmid22020127>{{cite journal |doi=10.1016/j.preteyeres.2011.10.001 |pmid=22020127 |pmc=3242826 |title=Electrical signaling in control of ocular cell behaviors |journal=Progress in Retinal and Eye Research |volume=31 |issue=1 |pages=65–88 |year=2012 |last1=Zhao |first1=Min |last2=Chalmers |first2=Laura |last3=Cao |first3=Lin |last4=Vieira |first4=Ana C |last5=Mannis |first5=Mark |last6=Reid |first6=Brian }}</ref>]]

[[File:MinZhaoImage2.jpg|thumb|Electric potential difference across corneal epithelium, and the generation of wound electric fields.<ref name=pmid22020127/>]]

[[File:Bioelectric potential modeled by Xenopus.png|thumb|Distribution of bioelectric potential in the flank of a frog embryo stained with voltage-sensitive fluorescent dye.<ref name=pmid28855098>{{cite journal |doi=10.1016/j.biosystems.2017.08.009 |pmid=28855098 |title=The bioelectric code: A old computational medium for dynamic control of growth and form |journal=Biosystems |volume=164 |pages=76–93 |year=2018 |last1=Levin |first1=Michael |last2=Martyniuk |first2=Christopher J |pmc=10464596 |doi-access=free }}</ref>]]

The inside/outside discontinuity at the cell surface enabled by a [[lipid bilayer]] membrane (capacitor) is at the core of bioelectricity. The plasma membrane was an indispensable structure for the origin and evolution of life itself. It provided compartmentalization permitting the setting of a differential voltage/potential gradient (battery or voltage source) across the [[membrane]], probably allowing early and rudimentary bioenergetics that fueled cell mechanisms.<ref>{{cite journal |pmid=20108228 |year=2010 |last1=Lane |first1=N |title=How did LUCA make a living? Chemiosmosis in the origin of life |journal=BioEssays |volume=32 |issue=4 |pages=271–280 |last2=Allen |first2=J. F |last3=Martin |first3=W |doi=10.1002/bies.200900131 }}</ref><ref>{{cite journal |pmid=23260134 |year=2012 |last1=Lane |first1=N |title=The origin of membrane bioenergetics |journal=Cell |volume=151 |issue=7 |pages=1406–16 |last2=Martin |first2=W. F |doi=10.1016/j.cell.2012.11.050 |doi-access=free }}</ref> During evolution, the initially purely passive diffusion of ions (charge carriers), become gradually controlled by the acquisition of [[ion channel]]s, [[Ion transporter|pumps]], exchangers, and transporters. These energetically free (resistors or conductors, passive transport) or expensive (current sources, active transport) translocators set and fine tune voltage gradients – resting potentials – that are ubiquitous and essential to life's physiology, ranging from bioenergetics, motion, sensing, nutrient transport, toxins clearance, and signaling in homeostatic and disease/injury conditions. Upon stimuli or barrier breaking (short-circuit) of the membrane, ions powered by the voltage gradient (electromotive force) diffuse or leak, respectively, through the [[cytoplasm]] and [[Extracellular fluid|interstitial fluids]] (conductors), generating measurable electric currents – net ion fluxes – and fields. Some ions (such as [[calcium]]) and molecules (such as [[hydrogen peroxide]]) modulate targeted translocators to produce a current or to enhance, mitigate or even reverse an initial current, being switchers.<ref name="ReferenceA">{{cite journal |pmid=24801267 |year=2014 |last1=Luxardi |first1=G |title=Single cell wound generates electric current circuit and cell membrane potential variations that requires calcium influx |journal=Integr. Biol. |volume=6 |issue=7 |pages=662–672 |last2=Reid |first2=B |last3=Maillard |first3=P |last4=Zhao |first4=M |doi=10.1039/c4ib00041b |s2cid=7313742 |url=http://www.escholarship.org/uc/item/2020237b }}</ref><ref name=pmid27827821>{{cite journal |doi=10.1242/dev.142034 |pmid=27827821 |pmc=5201032 |title=Early bioelectric activities mediate redox-modulated regeneration |journal=Development |volume=143 |issue=24 |pages=4582–4594 |year=2016 |last1=Ferreira |first1=Fernando |last2=Luxardi |first2=Guillaume |last3=Reid |first3=Brian |last4=Zhao |first4=Min }}</ref>

Endogenous bioelectric signals are produced in cells by the cumulative action of ion channels, pumps, and transporters. In non-excitable cells, the resting potential across the plasma membrane (Vmem) of individual cells propagate across distances via electrical synapses known as [[gap junction]]s (conductors), which allow cells to share their resting potential with neighbors. Aligned and stacked cells (such as in epithelia) generate transepithelial potentials (such as batteries in series) and electric fields, which likewise propagate across tissues.<ref>{{cite book |last1=Robinson |first1=K. |last2=Messerli |first2=M. |chapter=Electric Embryos: the embryonic epithelium as a generator of development information |editor1-last=McCaig |editor1-first=C |title=Nerve growth and guidance |pages=131–141 |publisher=Portland |year=1996 }}</ref> [[Tight junction]]s (resistors) efficiently mitigate the paracellular ion diffusion and leakage, precluding the voltage short circuit. Together, these voltages and electric fields form rich and dynamic and patterns inside living bodies that demarcate [[Morphology (biology)|anatomical features]], thus acting like blueprints for [[gene expression]] and morphogenesis in some instances. More than correlations, these bioelectrical distributions are dynamic, evolving with time and with the microenvironment and even long-distant conditions to serve as instructive influences over cell behavior and large-scale patterning during embryogenesis, regeneration, and cancer suppression.<ref name=pmid26566112/><ref>{{cite journal |pmid=29291972 |pmc=5753428 |year=2018 |last1=McLaughlin |first1=K. A |title=Bioelectric signaling in regeneration: Mechanisms of ionic controls of growth and form |journal=Developmental Biology |volume=433 |issue=2 |pages=177–189 |last2=Levin |first2=M |doi=10.1016/j.ydbio.2017.08.032 }}</ref><ref name=pmid28855098/><ref name=pmid28633567>{{cite journal |doi=10.1146/annurev-bioeng-071114-040647 |pmid=28633567 |title=Endogenous Bioelectric Signaling Networks: Exploiting Voltage Gradients for Control of Growth and Form |journal=Annual Review of Biomedical Engineering |volume=19 |pages=353–387 |year=2017 |last1=Levin |first1=Michael |last2=Pezzulo |first2=Giovanni |last3=Finkelstein |first3=Joshua M |pmc=10478168 }}</ref><ref>{{cite journal |first1=Emily |last1=Pitcairn |first2=Kelly A. |last2=McLaughlin |title=Bioelectric signaling coordinates patterning decisions during embryogenesis |journal=Trends in Developmental Biology |volume=9 |year=2016 |pages=1–9 |url=http://www.researchtrends.net/tia/abstract.asp?in=0&vn=9&tid=49&aid=5808&pub=2016&type= }}</ref> Bioelectric control mechanisms are an important emerging target for advances in regenerative medicine, [[birth defect]]s, cancer, and synthetic [[Biological engineering|bioengineering]].<ref>Pullar, C. E. The physiology of bioelectricity in development, tissue regeneration, and cancer.,  (CRC Press, 1996).{{page needed|date=May 2018}}</ref><ref>{{cite journal |pmid=14711011 |year=2003 |last1=Nuccitelli |first1=R |title=A role for endogenous electric fields in wound healing |journal=Current Topics in Developmental Biology |volume=58 |pages=1–26 |doi=10.1016/s0070-2153(03)58001-2 |isbn=978-0-12-153158-4 }}</ref>

== History ==

=== 18th century ===

Developmental bioelectricity began in the 18th century. Several seminal works stimulating muscle contractions using [[Leyden jar]]s culminated with the publication of classical studies by [[Luigi Galvani]] in 1791 (De viribus electricitatis in motu musculari) and 1794. In these, Galvani thought to have uncovered intrinsic electric-producing ability in living tissues or "animal electricity". [[Alessandro Volta]] showed that the frog's leg muscle twitching was due to a static electricity generator and from dissimilar metals undergoing or catalyzing [[Voltaic pile|electrochemical reactions]]. Galvani showed, in a 1794 study, twitching without metal electricity by touching the leg muscle with a deviating cut [[sciatic nerve]], definitively demonstrating "animal electricity".<ref>{{Cite book |last=Clarke, Edwin |title=Nineteenth-century origins of neuroscientific concepts |date=1987 |publisher=University of California Press |others=Jacyna, L. S. |isbn=0-520-05694-9|location=Berkeley |oclc=13456516}}</ref><ref>{{Cite book |last=Pera |first=Marcello |title=The ambiguous frog: the Galvani-Volta controversy on animal electricity |publisher=Princeton University Press|others=Tr. Mandelbaum, Jonathan |year=1992 |isbn=978-1-4008-6249-8 |location=Princeton, New Jersey |oclc=889251161}}</ref><ref>{{Cite book |last=Piccolino, Marco; Bresadola, Marco |title=Shocking frogs: Galvani, Volta, and the electric origins of neuroscience |publisher=Oxford University Press |year=2013 |isbn=978-0-19-978221-5 |location=Oxford; New York |oclc=859536612}}</ref> Unknowingly, Galvani with this and related experiments discovered the injury current (ion leakage driven by the intact membrane/epithelial potential) and injury potential (potential difference between injured and intact membrane/epithelium). The injury potential was, in fact, the electrical source behind the leg contraction, as realized in the next century.<ref>Maden, M. A history of regeneration research.  (Cambridge University Press, 1991).{{page needed|date=May 2018}}</ref><ref name=pmid15987799>{{cite journal |doi=10.1152/physrev.00020.2004 |pmid=15987799 |title=Controlling Cell Behavior Electrically: Current Views and Future Potential |journal=Physiological Reviews |volume=85 |issue=3 |pages=943–978 |year=2005 |last1=McCaig |first1=Colin D. |last2=Rajnicek |first2=Ann M |last3=Song |first3=Bing |last4=Zhao |first4=Min }}</ref> Subsequent work ultimately extended this field broadly beyond nerve and muscle to all cells, from bacteria to non-excitable mammalian cells.

=== 19th century ===

Building on earlier studies, further glimpses of developmental bioelectricity occurred with the discovery of wound-related electric currents and fields in the 1840s, when the [[electrophysiology|electrophysiologist]] [[Emil du Bois-Reymond]] reported macroscopic level electrical activities in frog, fish and human bodies. He recorded minute electric currents in live tissues and organisms with a then state-of-the-art [[galvanometer]] made of insulated copper wire coils. He unveiled the fast-changing electricity associated with muscle contraction and nerve excitation – the [[action potential]]s.<ref>{{cite journal |doi=10.1007/BF01640316 |title=Ueber den zeitlichen Verlauf der negativen Schwankung des Nervenstroms |trans-title=About the time course of the negative fluctuation of the nerve current |language=de |journal=Pflügers Archiv für die gesamte Physiologie des Menschen und der Tiere |volume=1 |issue=1 |pages=173–207 |year=1868 |last1=Bernstein |first1=J |s2cid=32435163 |url=https://zenodo.org/record/1682271 }}</ref><ref>{{cite journal |doi=10.1002/andp.18481511120 |title=Untersuchungen über thierische Elektricität |trans-title=Investigations on animal electricity |language=de |journal=Annalen der Physik und Chemie |volume=151 |issue=11 |pages=463–464 |year=1848 |last1=Du Bois-Reymond |first1=Emil |bibcode=1848AnP...151..463D |url=https://zenodo.org/record/2488437 }}</ref><ref>{{cite journal |doi=10.1016/0166-2236(83)90078-4 |title=The discovery of the action potential |journal=Trends in Neurosciences |volume=6 |pages=164–8 |year=1983 |last1=Schuetze |first1=Stephen M |s2cid=53175297 }}</ref> Du Bois-Reymond also reported in detail less fluctuating electricity at wounds – injury current and potential – he made to himself.<ref>{{cite book |last1=Du Bois-Reymond |first1=Emil |title=Untersuchungen uber thierische Elektricitat |trans-title=Investigations on Animal Electricity |language=de |location=Berlin |publisher=Georg Reimer |year=1860 }}{{page needed|date=May 2018}}</ref><ref>{{Cite book |last=Finkelstein |first=Gabriel |title=Emil du Bois-Reymond: neuroscience, self, and society in nineteenth-century Germany |publisher=The MIT Press |year=2013 |isbn=978-1-4619-5032-5 |oclc=864592470}}</ref>

[[File:Levin Figure 5.png|thumb|upright=1.75|Some sample cell types and their resting potentials, revealing that actively proliferating and plastic cells cluster in the depolarized end of the continuum, while terminally-differentiated mature cell types tend to be strongly polarized.<ref name=pmid22809139>{{cite journal |doi=10.1146/annurev-bioeng-071811-150114 |pmid=22809139 |title=Regulation of Cell Behavior and Tissue Patterning by Bioelectrical Signals: Challenges and Opportunities for Biomedical Engineering |journal=Annual Review of Biomedical Engineering |volume=14 |pages=295–323 |year=2012 |last1=Levin |first1=Michael |last2=Stevenson |first2=Claire G |pmc=10472538 }}</ref>]]

=== Early 20th century ===

Developmental bioelectricity work began in earnest at the beginning of the 20th century.<ref>{{cite journal |doi=10.1152/ajplegacy.1903.8.4.294 |title=Electrical Polarity in the Hydroids |journal=American Journal of Physiology. Legacy Content |volume=8 |issue=4 |pages=294–299 |year=1903 |last1=Mathews |first1=Albert P. }}</ref> Ida H. Hyde studied the role of electricity in the development of eggs.<ref>{{cite journal |last1=Hyde |first1=Ida H. |title=Differences in Electrical Potential in Developing Eggs |journal=American Journal of Physiology. Legacy Content |volume=12 |issue=3 |pages=241–275 |year=1904 |doi=10.1152/ajplegacy.1904.12.3.241}}</ref>
T. H. Morgan and others studied the electrophysiology of the earthworm.<ref>{{cite journal |last1=Morgan |first1=T. H. |last2=Dimon |first2=Abigail C. |title=An examination of the problems of physiological "polarity" and of electrical polarity in the earthworm |journal=Journal of Experimental Zoology |volume=1 |issue=2 |page=331 |year=1904 |hdl=2027/hvd.32044107333023 |hdl-access=free  |doi=10.1002/jez.1400010206|bibcode=1904JEZ.....1..331M }}</ref>
Oren E. Frazee studied the effects of electricity on limb regeneration in amphibians.<ref>{{cite journal |last1=Frazee |first1=Oren E. |title=The effect of electrical stimulation upon the rate of regeneration in Rana pipiens and Amblystoma jeffersonianum |journal=Journal of Experimental Zoology |volume=7 |issue=3 |pages=457–475 |year=1909 |doi=10.1002/jez.1400070304 |bibcode=1909JEZ.....7..457F }}</ref>
E. J. Lund explored morphogenesis in flowering plants.<ref>{{cite journal |last1=Lund |first1=E. J. |title=Reversibility of morphogenetic processes in Bursaria |journal=Journal of Experimental Zoology |volume=24 |pages=1–33 |year=1917 |issue=1 |doi=10.1002/jez.1400240102|bibcode=1917JEZ....24....1L }}</ref>
[[Libbie Hyman]] studied vertebrate and invertebrate animals.<ref>{{Cite book |last=Hyman |first=Libbie Henrietta |url=https://books.google.com/books?id=VKlWjdOkiMwC |title=Hyman's Comparative Vertebrate Anatomy |date=1992-09-15 |publisher=University of Chicago Press |isbn=978-0-226-87013-7 |pages=192–236}}</ref><ref>{{cite journal |last=Hyman |first=Libbie Henrietta |author-link=Libbie Hyman |title=Special Articles |journal=Science |volume=48 |issue=1247 |pages=518–524 |year=1918 |doi=10.1126/science.48.1247.518 |pmid=17795612}}</ref> 

In the 1920s and 1930s, [[Elmer J. Lund]]<ref>Lund, E. Bioelectric fiends and growth, (University of Texas Press, 1947).{{page needed|date=May 2018}}</ref> and [[Harold Saxton Burr]]<ref>{{cite journal |doi=10.1086/394488 |jstor=2808474 |title=The Electro-Dynamic Theory of Life |journal=The Quarterly Review of Biology |volume=10 |issue=3 |pages=322–333 |year=1935 |last1=Burr |first1=H. S. |last2=Northrop |first2=F. S. C. |s2cid=84480134 }}</ref> wrote multiple papers about the role of electricity in embryonic development.<ref name=pmid22809139/> Lund measured currents in a large number of living model systems, correlating them to changes in patterning. In contrast, Burr used a voltmeter to measure voltage gradients, examining developing embryonic tissues and tumors, in a range of animals and plants. Applied electric fields were demonstrated to alter the regeneration of [[planarian]] by Marsh and Beams in the 1940s and 1950s,<ref>{{cite journal |last1=Marsh |first1=G. |first2=H. W. |last2=Beams |title=Electrical control of axial polarity in a regenerating annelid |journal=Anatomical Record |year=1949 |volume=105 |issue=3 |pages=513–514 }}</ref><ref>{{cite journal |pmid=20342775 |year=1947 |last1=Marsh |first1=G. |title=Electrical control of growth polarity in regenerating Dugesia tigrina |journal=Federation Proceedings |volume=6 |issue=1 Pt 2 |page=163 |last2=Beams |first2=H. W. }}</ref> inducing the formation of heads or tails at cut sites, reversing the primary body polarity.

=== Late 20th century ===

In the 1970s, Lionel Jaffe and Richard Nuccittelli's introduction and development of the vibrating probe, the first device for quantitative non-invasive characterization of the extracellular minute ion currents, revitalized the field.<ref name=pmid4421919>{{cite journal |doi=10.1083/jcb.63.2.614 |pmid=4421919 |pmc=2110946 |title=An Ultrasensitive Vibrating Probe for Measuring Steady Extracellular Currents |journal=The Journal of Cell Biology |volume=63 |issue=2 |pages=614–28 |year=1974 |last1=Jaffe |first1=Lionel F. |last2=Nuccitelli |first2=Richard }}</ref><ref>{{cite book |last1=Jaffe |first1=L. |chapter=Developmental Currents Voltages and Gradients |pages=[https://archive.org/details/developmentalord0000subt/page/183 183–215] |title=Developmental Order, Its Origin and Regulation |year=1982 |isbn=978-0-8451-1501-5 |chapter-url-access=registration |chapter-url=https://archive.org/details/developmentalord0000subt/page/183 }}</ref><ref name=pmid6117911>{{cite journal |doi=10.1098/rstb.1981.0160 |pmid=6117911 |jstor=2395645 |title=The Role of Ionic Currents in Establishing Developmental Pattern |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=295 |issue=1078 |pages=553–566 |year=1981 |last1=Jaffe |first1=L. F |bibcode=1981RSPTB.295..553J |doi-access=free }}</ref><ref>{{cite book |last1=Nuccitelli |first1=Richard |doi=10.1021/ba-1995-0250.ch007 |chapter=Endogenous Electric Fields Measured in Developing Embryos |title=Electromagnetic Fields |volume=250 |pages=109–24 |series=Advances in Chemistry |year=1995 |isbn=978-0-8412-3135-1 }}</ref><ref name=pmid326151>{{cite journal |doi=10.1146/annurev.bb.06.060177.002305 |pmid=326151 |title=Electrical Controls of Development |journal=Annual Review of Biophysics and Bioengineering |volume=6 |pages=445–476 |year=1977 |last1=Jaffe |first1=L. F. |last2=Nuccitelli |first2=R. }}</ref>
 
Researchers such as Joseph Vanable, Richard Borgens, Ken Robinson, and Colin McCaig explored the roles of endogenous bioelectric signaling in limb development and regeneration, embryogenesis, organ polarity, and [[wound healing]].<ref>{{cite journal |pmid=3960913 |year=1986 |last1=Borgens |first1=R. B |title=The role of natural and applied electric fields in neuronal regeneration and development |journal=Progress in Clinical and Biological Research |volume=210 |pages=239–250 }}</ref>
<ref>{{cite book |last1=Borgens |first1=Richard B. |chapter=What Is the Role of Naturally Produced Electric Current in Vertebrate Regeneration and Healing? |volume=76 |pages=245–298 |year=1982 |title=International Review of Cytology Volume 76 |isbn=978-0-12-364476-3 |doi=10.1016/S0074-7696(08)61793-3 |pmid=6749746 }}</ref>
<ref name=pmid15987799/><ref>{{cite journal |last1=McCaig |first1=Colin D. |last2=Rajnicek |first2=Ann M. |last3=Song |first3=Bing |last4=Zhao |first4=Min |title=Has electrical growth cone guidance found its potential? |journal=Trends in Neurosciences |volume=25 |issue=7 |pages=354–9 |year=2002 |s2cid=7534545 |doi=10.1016/S0166-2236(02)02174-4 |pmid=12079763 }}</ref> 

C.D. Cone studied the role of resting potential in regulating [[Cellular differentiation|cell differentiation]] and proliferation.<ref>{{cite journal |doi=10.1159/000224567 |pmid=5148061 |title=Control of Somatic Cell Mitosis by Simulated Changes in the Transmembrane Potential Level |journal=Oncology |volume=25 |issue=2 |pages=168–182 |year=1971 |last1=Cone |first1=C. D. Jr |last2=Tongier |first2=M. Jr }}</ref><ref>{{cite journal |doi=10.1038/newbio246110a0 |pmid=4518935 |title=Stimulation of DNA Synthesis in CNS Neurones by Sustained Depolarisation |journal=Nature New Biology |volume=246 |issue=152 |pages=110–111 |year=1973 |last1=Stillwell |first1=E. F. |last2=Cone |first2=C. M. |last3=Cone |first3=C. D. }}</ref> 
Subsequent work has identified specific regions of the resting potential spectrum that correspond to distinct cell states such as quiescent, stem, cancer, and terminally differentiated.<ref>{{cite journal |doi=10.1016/S0022-5193(86)80209-0 |pmid=2443763 |title=Membrane potentials and sodium channels: Hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions |journal=Journal of Theoretical Biology |volume=123 |issue=4 |pages=377–401 |year=1986 |last1=Binggeli |first1=Richard |last2=Weinstein |first2=Roy C. |bibcode=1986JThBi.123..377B }}</ref>

Although this body of work generated a significant amount of high-quality physiological data, this large-scale biophysics approach has historically come second to the study of biochemical gradients and genetic networks in biology education, funding, and overall popularity among biologists. A key factor that contributed to this field lagging behind molecular genetics and biochemistry is that bioelectricity is inherently a living phenomenon – it cannot be studied in fixed specimens. Working with bioelectricity is more complex than traditional approaches to developmental biology, both methodologically and conceptually, as it typically requires a highly interdisciplinary approach.<ref name=pmid28633567/>

== Study techniques ==

=== Electrodes ===

The gold standard techniques to quantitatively extract electric dimensions from living specimens, ranging from cell to organism levels, are the glass microelectrode (or [[micropipette]]), the vibrating (or self-referencing) voltage probe, and the vibrating ion-selective [[microelectrode]]. The former is inherently invasive, and the two latter are non-invasive, but all are ultra-sensitive<ref>{{cite journal |doi=10.1038/144710a0 |title=Action Potentials Recorded from Inside a Nerve Fibre |journal=Nature |volume=144 |issue=3651 |page=710 |year=1939 |last1=Hodgkin |first1=A. L |last2=Huxley |first2=A. F |bibcode=1939Natur.144..710H |s2cid=4104520 }}</ref> and fast-responsive sensors extensively used in a plethora of physiological conditions in widespread biological models.<ref name=pmid24671205>{{cite journal |doi=10.1371/journal.pone.0092594 |pmid=24671205 |pmc=3966808 |title=V-ATPase Proton Pumping Activity is Required for Adult Zebrafish Appendage Regeneration |journal=PLOS ONE |volume=9 |issue=3 |pages=e92594 |year=2014 |last1=Monteiro |first1=Joana |last2=Aires |first2=Rita |last3=Becker |first3=Jörg D |last4=Jacinto |first4=António |last5=Certal |first5=Ana C |last6=Rodríguez-León |first6=Joaquín |bibcode=2014PLoSO...992594M |doi-access=free }}</ref><ref>{{cite book |doi=10.1007/978-3-540-37843-3_5 |chapter=Use of Non-Invasive Ion-Selective Microelectrode Techniques for the Study of Plant Development |title=Plant Electrophysiology |pages=109–137 |year=2006 |last1=Kunkel |first1=Joseph G |last2=Cordeiro |first2=Sofia |last3=Xu |first3=Yu (Jeff) |last4=Shipley |first4=Alan M |last5=Feijó |first5=José A |isbn=978-3-540-32717-2 }}</ref><ref name="ReferenceA"/><ref>{{cite journal |pmid=27283241 |pmc=4901296 |year=2016 |last1=Shen |first1=Y |title=Diabetic cornea wounds produce significantly weaker electric signals that may contribute to impaired healing |journal=Scientific Reports |volume=6 |page=26525 |last2=Pfluger |first2=T |last3=Ferreira |first3=F |last4=Liang |first4=J |last5=Navedo |first5=M. F |last6=Zeng |first6=Q |last7=Reid |first7=B |last8=Zhao |first8=M |doi=10.1038/srep26525 |bibcode=2016NatSR...626525S }}</ref><ref name=pmid15987799/>{{excessive citations inline|date=November 2023}}

The glass microelectrode was developed in the 1940s to study the action potential of excitable cells, deriving from the seminal work by Hodgkin and Huxley in the [[squid giant axon|giant axon squid]].<ref>{{cite journal |doi=10.1038/144710a0 |title=Action Potentials Recorded from Inside a Nerve Fibre |journal=Nature |volume=144 |issue=3651 |pages=710–711 |year=1939 |last1=Hodgkin |first1=A. L |last2=Huxley |first2=A. F |bibcode=1939Natur.144..710H |s2cid=4104520 }}</ref><ref>{{cite journal |doi=10.1002/jcp.1030280106 |pmid=21002959 |title=Membrane potentials and excitation of impaled single muscle fibers |journal=Journal of Cellular and Comparative Physiology |volume=28 |issue=1 |pages=99–117 |year=1946 |last1=Graham |first1=Judith |last2=Gerard |first2=R. W |s2cid=45361295 }}</ref> It is simply a liquid [[salt bridge]] connecting the biological specimen with the electrode, protecting tissues from leachable toxins and [[redox]] reactions of the bare electrode. Owing to its low impedance, low junction potential and weak polarization, silver electrodes are standard transducers of the ionic into electric current that occurs through a reversible redox reaction at the electrode surface.<ref>{{cite journal |doi=10.1243/17403499JNN149 |title=Patch clamp technique: Review of the current state of the art and potential contributions from nanoengineering |journal=Proceedings of the Institution of Mechanical Engineers, Part N: Journal of Nanoengineering and Nanosystems |volume=222 |pages=1–11 |year=2009 |last1=Zhao |first1=Y |last2=Inayat |first2=S |last3=Dikin |first3=D A |last4=Singer |first4=J H |last5=Ruoff |first5=R S |last6=Troy |first6=J B |s2cid=53316098 }}</ref>

The vibrating probe was introduced in biological studies in the 1970s.<ref name=pmid314968>{{cite journal |doi=10.1002/jez.1402090106 |pmid=314968 |title=Role of subdermal current shunts in the failure of frogs to regenerate |journal=Journal of Experimental Zoology |volume=209 |issue=1 |pages=49–56 |year=1979 |last1=Borgens |first1=Richard B |last2=Vanable |first2=Joseph W |last3=Jaffe |first3=Lionel F |bibcode=1979JEZ...209...49B }}</ref><ref name=pmid301554>{{cite journal |doi=10.1002/jez.1402000310 |pmid=301554 |title=Bioelectricity and regeneration. I. Initiation of frog limb regeneration by minute currents |journal=Journal of Experimental Zoology |volume=200 |issue=3 |pages=403–416 |year=1977 |last1=Borgens |first1=R. B |last2=Vanable |first2=J. W |last3=Jaffe |first3=L. F |bibcode=1977JEZ...200..403B }}</ref><ref name=pmid4421919/> The voltage-sensitive probe is electroplated with platinum to form a capacitive black tip ball with large surface area. When vibrating in an artificial or natural DC voltage gradient, the capacitive ball oscillates in a sinusoidal AC output. The amplitude of the wave is proportional to the measuring potential difference at the frequency of the vibration, efficiently filtered by a lock-in amplifier that boosts probe's sensitivity.<ref name=pmid4421919/><ref name="Shipley & Feijó 1999">{{cite book |doi=10.1007/978-3-642-59969-9_17 |chapter=The Use of the Vibrating Probe Technique to Study Steady Extracellular Currents During Pollen Germination and Tube Growth |title=Fertilization in Higher Plants |pages=235–252 |year=1999 |last1=Shipley |first1=A. M |last2=Feijó |first2=J. A |isbn=978-3-642-64202-9 }}</ref><ref name=pmid17406628>{{cite journal |doi=10.1038/nprot.2007.91 |pmid=17406628 |title=Non-invasive measurement of bioelectric currents with a vibrating probe |journal=Nature Protocols |volume=2 |issue=3 |pages=661–669 |year=2007 |last1=Reid |first1=Brian |last2=Nuccitelli |first2=Richard |last3=Zhao |first3=Min |s2cid=15237787 }}</ref>

The vibrating ion-selective microelectrode was first used in 1990 to measure calcium fluxes in various cells and tissues.<ref>{{cite journal | last1=Kuhtreiber | first1=W. M. | last2=Jaffe | first2=L. F. | year=1990 | title=Detection of extracellular calcium gradients with a calcium-specific vibrating electrode | pmc=2200169 | journal=J Cell Biol | volume=110 | issue=5| pages=1565–1573 | pmid=2335563 | doi=10.1083/jcb.110.5.1565 }}</ref> The ion-selective microelectrode is an adaptation of the glass microelectrode, where an ion-specific liquid ion exchanger (ionophore) is tip-filled into a previously silanized (to prevent leakage) microelectrode. Also, the microelectrode vibrates at low frequencies to operate in the accurate self-referencing mode. Only the specific ion permeates the [[ionophore]], therefore the voltage readout is proportional to the ion concentration in the measuring condition. Then, flux is calculated using the [[Fick's laws of diffusion|Fick's first law]].<ref name="Shipley & Feijó 1999"/><ref name=pmid25993490>{{cite journal |doi=10.3791/52782 |pmid=25993490 |pmc=4541607 |title=Measurement of Extracellular Ion Fluxes Using the Ion-selective Self-referencing Microelectrode Technique |journal=Journal of Visualized Experiments |issue=99 |pages=e52782 |year=2015 |last1=Luxardi |first1=Guillaume |last2=Reid |first2=Brian |last3=Ferreira |first3=Fernando |last4=Maillard |first4=Pauline |last5=Zhao |first5=Min }}</ref>

Emerging optic-based techniques,<ref name=pmid22341329>{{cite book |doi=10.1016/B978-0-444-59426-6.00012-4 |pmid=22341329 |pmc=3494096 |chapter=Optogenetic reporters |title=Optogenetics: Tools for Controlling and Monitoring Neuronal Activity |volume=196 |pages=235–263 |series=Progress in Brain Research |year=2012 |last1=Tantama |first1=Mathew |last2=Hung |first2=Yin Pun |last3=Yellen |first3=Gary |isbn=978-0-444-59426-6 }}</ref> for example, the [[pH]] optrode (or [[optode]]), which can be integrated into a self-referencing system may become an alternative or additional technique in bioelectricity laboratories. The optrode does not require referencing and is insensitive to electromagnetism<ref name=pmid19823237>{{cite journal |doi=10.1364/AO.48.005528 |pmid=19823237 |title=Frequency-domain fluorescence lifetime optrode system design and instrumentation without a concurrent reference light-emitting diode |journal=Applied Optics |volume=48 |issue=29 |pages=5528–5536 |year=2009 |last1=Chatni |first1=Mohammad Rameez |last2=Li |first2=Gang |last3=Porterfield |first3=David Marshall |bibcode=2009ApOpt..48.5528C }}</ref> simplifying system setting up and making it a suitable option for recordings where electric stimulation is simultaneously applied.

Much work to functionally study bioelectric signaling has made use of applied (exogenous) electric currents and fields via DC and AC voltage-delivering apparatus integrated with agarose salt bridges.<ref>{{cite journal |doi=10.1038/nprot.2007.205 |pmid=17545984 |title=Application of direct current electric fields to cells and tissues in vitro and modulation of wound electric field in vivo |journal=Nature Protocols |volume=2 |issue=6 |pages=1479–1489 |year=2007 |last1=Song |first1=Bing |last2=Gu |first2=Yu |last3=Pu |first3=Jin |last4=Reid |first4=Brian |last5=Zhao |first5=Zhiqiang |last6=Zhao |first6=Min |s2cid=25924011 }}</ref> These devices can generate countless combinations of voltage magnitude and direction, pulses, and frequencies. Currently, lab-on-a-chip mediated application of electric fields is gaining ground in the field with the possibility to allow high-throughput screening assays of the large combinatory outputs.<ref>{{cite journal |doi=10.1039/C4LC00745J |pmid=25242672 |pmc=4437771 |title=ElectroTaxis-on-a-Chip (ETC): An integrated quantitative high-throughput screening platform for electrical field-directed cell migration |journal=Lab Chip |volume=14 |issue=22 |pages=4398–4405 |year=2014 |last1=Zhao |first1=Siwei |last2=Zhu |first2=Kan |last3=Zhang |first3=Yan |last4=Zhu |first4=Zijie |last5=Xu |first5=Zhengping |last6=Zhao |first6=Min |last7=Pan |first7=Tingrui |url=http://www.escholarship.org/uc/item/06s2n9m6 }}</ref>

[[File:Supplemental Fig. 2.png|thumb|upright=2|Tools for manipulating non-neural bioelectricity include pharmacological and genetic reagents to alter cell connectivity (control gap junctions), cell V<sub>mem</sub> (control ion channels/pumps), and bioelectrically guided 2nd messengers (control neurotransmitters and other small molecules).<ref name=pmid27574538>{{cite journal |doi=10.1080/19420889.2016.1192733 |pmid=27574538 |pmc=4988443 |title=Physiological inputs regulate species-specific anatomy during embryogenesis and regeneration |journal=Communicative & Integrative Biology |volume=9 |issue=4 |pages=e1192733 |year=2016 |last1=Sullivan |first1=Kelly G |last2=Emmons-Bell |first2=Maya |last3=Levin |first3=Michael }}</ref>]]

=== Fluorescence ===

Progress in molecular biology over the last six decades has produced powerful tools that facilitate the dissection of biochemical and genetic signals; yet, they tend to not be well-suited for bioelectric studies ''in vivo''. Prior work relied extensively on current applied directly by electrodes, reinvigorated by significant recent advances in materials science<ref>{{cite book |doi=10.1109/DELTA.2010.60 |chapter=Detection of Electrical Activity of Pancreatic Beta-cells Using Micro-electrode Arrays |title=2010 Fifth IEEE International Symposium on Electronic Design, Test & Applications |pages=233–236 |year=2010 |last1=Bornat |first1=Yannick |last2=Raoux |first2=Matthieu |last3=Boutaib |first3=Youssef |last4=Morin |first4=Fabrice |last5=Charpentier |first5=Gilles |last6=Lang |first6=Jochen |last7=Renaud |first7=Sylvie |display-authors=3 |isbn=978-1-4244-6025-0 |s2cid=12107878 |url=https://hal.archives-ouvertes.fr/hal-00501820/file/DELTA_2010_Bornat.pdf }}</ref><ref>{{cite journal |doi=10.1016/0168-1656(91)90241-M |pmid=1367098 |title=Electrically controlled proliferation of human carcinoma cells cultured on the surface of an electrode |journal=Journal of Biotechnology |volume=18 |issue=1–2 |pages=129–139 |year=1991 |last1=Kojima |first1=Junichiro |last2=Shinohara |first2=Hiroaki |last3=Ikariyama |first3=Yosihito |last4=Aizawa |first4=Masuo |last5=Nagaike |first5=Kazuhiro |last6=Morioka |first6=Satoshi |display-authors=3}}</ref><ref>{{cite journal |doi=10.1002/btpr.609 |pmid=21574266 |pmc=4557870 |title=Skeletal myotube integration with planar microelectrode arrays in vitro for spatially selective recording and stimulation: A comparison of neuronal and myotube extracellular action potentials |journal=Biotechnology Progress |volume=27 |issue=3 |pages=891–5 |year=2011 |last1=Langhammer |first1=Christopher G |last2=Kutzing |first2=Melinda K |last3=Luo |first3=Vincent |last4=Zahn |first4=Jeffrey D |last5=Firestein |first5=Bonnie L |display-authors=3}}</ref><ref>{{cite journal |doi=10.1089/ten.tec.2009.0751 |pmid=20367249 |pmc=3003917 |title=Application of Low-Frequency Alternating Current Electric Fields Via Interdigitated Electrodes: Effects on Cellular Viability, Cytoplasmic Calcium, and Osteogenic Differentiation of Human Adipose-Derived Stem Cells |journal=Tissue Engineering Part C: Methods |volume=16 |issue=6 |pages=1377–86 |year=2010 |last1=McCullen |first1=Seth D |last2=McQuilling |first2=John P |last3=Grossfeld |first3=Robert M |last4=Lubischer |first4=Jane L |last5=Clarke |first5=Laura I |last6=Loboa |first6=Elizabeth G |display-authors=3}}</ref><ref>{{cite journal |doi=10.1016/j.bios.2010.06.068 |pmid=20656468 |title=DC microelectrode array for investigating the intracellular ion changes |journal=Biosensors and Bioelectronics |volume=26 |issue=4 |pages=1268–1272 |year=2010 |last1=Aryasomayajula |first1=Aditya |last2=Derix |first2=Jonathan |last3=Perike |first3=Srikant |last4=Gerlach |first4=Gerald |last5=Funk |first5=R.H }}</ref><ref>{{cite journal |doi=10.1002/smll.201700789 |pmid=28556571 |pmc=5560653 |title=Controlling the Resting Membrane Potential of Cells with Conducting Polymer Microwires |journal=Small |volume=13 |issue=27 |page=1700789 |year=2017 |last1=Jayaram |first1=Dhanya T |last2=Luo |first2=Qingjie |last3=Thourson |first3=Scott B |last4=Finlay |first4=Adam H |last5=Payne |first5=Christine K }}</ref>{{excessive citations inline|date=November 2023}} and extracellular current measurements, facilitated by sophisticated self-referencing electrode systems.<ref>{{cite journal |doi=10.1002/(SICI)1097-0029(19990915)46:6<398::AID-JEMT8>3.0.CO;2-H |pmid=10504217 |title=Self-referencing, non-invasive, ion selective electrode for single cell detection of trans-plasma membrane calcium flux |journal=Microscopy Research and Technique |volume=46 |issue=6 |pages=398–417 |year=1999 |last1=Smith |first1=Peter J.S |last2=Hammar |first2=Katherine |last3=Porterfield |first3=D. Marshall |last4=Sanger |first4=Richard H |last5=Trimarchi |first5=James R |s2cid=25177705 }}</ref><ref>{{cite book |first1=Peter J. S. |last1=Smith |first2=Richard H. |last2=Sanger |first3=Mark A. |last3=Messerli |chapter=Principles, Development and Applications of Self-Referencing Electrochemical Microelectrodes to the Determination of Fluxes at Cell Membranes |chapter-url={{Google books|WdPLBQAAQBAJ|page=373|plainurl=yes}} |pages=373–405 |editor1-first=Adrian C. |editor1-last=Michael |editor2-first=Laura |editor2-last=Borland |title=Electrochemical Methods for Neuroscience |year=2006 |publisher=CRC |pmid=21204387 |isbn=978-1-4200-0586-8 }}</ref> While electrode applications for manipulating neuraly-controlled body processes have recently attracted much attention,<ref>{{cite journal |doi=10.1038/nm0613-654 |pmid=23744134 |title=Charged by GSK investment, battery of electroceuticals advance |journal=Nature Medicine |volume=19 |issue=6 |page=654 |year=2013 |last1=Sinha |first1=Gunjan |s2cid=2260750 |doi-access=free }}</ref><ref>{{cite journal |doi=10.1038/496159a |pmid=23579662 |pmc=4179459 |title=A jump-start for electroceuticals |journal=Nature |volume=496 |issue=7444 |pages=159–161 |year=2013 |last1=Famm |first1=Kristoffer |last2=Litt |first2=Brian |last3=Tracey |first3=Kevin J |last4=Boyden |first4=Edward S |author5=[[Moncef Slaoui|Slaoui, Moncef]]}}</ref> there are other opportunities for controlling somatic processes, as most cell types are electrically active and respond to ionic signals from themselves and their neighbors.

In the early part of the 21st century, a number of new molecular techniques were developed that allowed bioelectric pathways to be investigated with a high degree of mechanistic resolution, and to be linked to canonical molecular cascades.<ref name=pmid25896279>{{cite journal |doi=10.1387/ijdb.140207ml |pmid=25896279 |title=Optogenetics in Developmental Biology: Using light to control ion flux-dependent signals in Xenopus embryos |journal=The International Journal of Developmental Biology |volume=58 |issue=10–12 |pages=851–861 |year=2014 |last1=Spencer Adams |first1=Dany |last2=Lemire |first2=Joan M. |last3=Kramer |first3=Richard H. |last4=Levin |first4=Michael |pmc=10468825 |doi-access=free }}</ref> These include:
#Pharmacological screens to identify endogenous channels and pumps responsible for specific patterning events;<ref name=pmid17078061>{{cite journal |doi=10.1002/dvg.20246 |pmid=17078061 |pmc=3142945 |title=Inverse drug screens: A rapid and inexpensive method for implicating molecular targets |journal=Genesis |volume=44 |issue=11 |pages=530–540 |year=2006 |last1=Adams |first1=Dany S |last2=Levin |first2=Michael }}</ref><ref name=pmid16554361>{{cite journal |doi=10.1242/dev.02341 |pmid=16554361 |pmc=3136117 |title=Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates |journal=Development |volume=133 |issue=9 |pages=1657–1671 |year=2006 |last1=Adams |first1=D. S. |last2=Robinson |first2=K. R. |last3=Fukumoto |first3=T. |last4=Yuan |first4=S |last5=Albertson |first5=R. C. |last6=Yelick |first6=P |last7=Kuo |first7=L. |last8=McSweeney |first8=M. |last9=Levin |first9=M. }}</ref><ref name=pmid22350846>{{cite journal |doi=10.1007/s00441-012-1329-4 |pmid=22350846 |pmc=3869965 |title=Endogenous voltage gradients as mediators of cell-cell communication: Strategies for investigating bioelectrical signals during pattern formation |journal=Cell and Tissue Research |volume=352 |issue=1 |pages=95–122 |year=2012 |last1=Adams |first1=Dany S |last2=Levin |first2=Michael }}</ref>
#Voltage-sensitive fluorescent reporter dyes and genetically encoded fluorescent voltage indicators for the characterization of the bioelectric state in vivo.<ref name=pmid22474653>{{cite journal |doi=10.1101/pdb.top067710 |pmid=22474653 |pmc=4001120 |title=General Principles for Measuring Resting Membrane Potential and Ion Concentration Using Fluorescent Bioelectricity Reporters |journal=Cold Spring Harbor Protocols |volume=2012 |issue=4 |pages=385–397 |year=2012 |last1=Adams |first1=D. S |last2=Levin |first2=M }}</ref><ref name=pmid22474652>{{cite journal |doi=10.1101/pdb.prot067702 |pmid=22474652 |pmc=4001116 |title=Measuring Resting Membrane Potential Using the Fluorescent Voltage Reporters DiBAC4(3) and CC2-DMPE |journal=Cold Spring Harbor Protocols |volume=2012 |issue=4 |pages=459–464 |year=2012 |last1=Adams |first1=D. S |last2=Levin |first2=M }}</ref><ref name=pmid6704395>{{cite journal |doi=10.1016/0005-2736(84)90535-2 |pmid=6704395 |title=Comparative measurements of membrane potentials with microelectrodes and voltage-sensitive dyes |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |volume=771 |issue=2 |pages=208–216 |year=1984 |last1=Bräuner |first1=Thomas |last2=Hülser |first2=Dieter F |last3=Strasser |first3=Reto J |url=http://nbn-resolving.de/urn:nbn:de:bsz:93-opus-68610 }}</ref><ref name=pmid27428174>{{cite journal |doi=10.1021/jacs.6b05672 |pmid=27428174 |pmc=5222532 |title=Isomerically Pure Tetramethylrhodamine Voltage Reporters |journal=Journal of the American Chemical Society |volume=138 |issue=29 |pages=9085–9088 |year=2016 |last1=Deal |first1=Parker E |last2=Kulkarni |first2=Rishikesh U |last3=Al-Abdullatif |first3=Sarah H |last4=Miller |first4=Evan W }}</ref><ref name=pmid21356693>{{cite journal |doi=10.1101/pdb.prot5055 |pmid=21356693 |title=Live Imaging of Planarian Membrane Potential Using DiBAC4(3) |journal=Cold Spring Harbor Protocols |volume=2008 |issue=11 |pages=pdb.prot5055 |year=2008 |last1=Oviedo |first1=N. J |last2=Nicolas |first2=C. L |last3=Adams |first3=D. S |last4=Levin |first4=M |pmc=10468776 }}</ref> 
#Panels of well-characterized dominant ion channels that can be misexpressed in cells of interest to alter the bioelectric state in desired ways;<ref name=pmid22350846/><ref name=pmid22159581>{{cite journal |doi=10.1242/dev.073759 |pmid=22159581 |pmc=3243095 |title=Transmembrane voltage potential controls embryonic eye patterning in Xenopus laevis |journal=Development |volume=139 |issue=2 |pages=313–323 |year=2011 |last1=Pai |first1=V. P |last2=Aw |first2=S |last3=Shomrat |first3=T |last4=Lemire |first4=J. M |last5=Levin |first5=M }}</ref><ref name=pmid29519998>{{cite journal |doi=10.1038/s41467-018-03334-5 |pmid=29519998 |pmc=5843655 |title=HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns |journal=Nature Communications |volume=9 |issue=1 |page=998 |year=2018 |last1=Pai |first1=Vaibhav P |last2=Pietak |first2=Alexis |last3=Willocq |first3=Valerie |last4=Ye |first4=Bin |last5=Shi |first5=Nian-Qing |last6=Levin |first6=Michael |bibcode=2018NatCo...9..998P }}</ref> and 
#Computational platforms that are coming on-line<ref name=pmid27458581>{{cite journal |doi=10.3389/fbioe.2016.00055 |pmid=27458581 |pmc=4933718 |title=Exploring Instructive Physiological Signaling with the Bioelectric Tissue Simulation Engine |journal=Frontiers in Bioengineering and Biotechnology |volume=4 |page=55 |year=2016 |last1=Pietak |first1=Alexis |last2=Levin |first2=Michael |doi-access=free }}</ref><ref name=pmid28954851>{{cite journal |doi=10.1098/rsif.2017.0425 |pmid=28954851 |pmc=5636277 |title=Bioelectric gene and reaction networks: Computational modelling of genetic, biochemical and bioelectrical dynamics in pattern regulation |journal=Journal of the Royal Society Interface |volume=14 |issue=134 |page=20170425 |year=2017 |last1=Pietak |first1=Alexis |last2=Levin |first2=Michael }}</ref> to assist in building predictive models of bioelectric dynamics in tissues.<ref name=pmid26841954>{{cite journal |doi=10.1038/srep20403 |pmid=26841954 |pmc=4740742 |title=Bioelectrical Signals and Ion Channels in the Modeling of Multicellular Patterns and Cancer Biophysics |journal=Scientific Reports |volume=6 |page=20403 |year=2016 |last1=Cervera |first1=Javier |last2=Alcaraz |first2=Antonio |last3=Mafe |first3=Salvador |bibcode=2016NatSR...620403C }}</ref><ref name=pmid27731412>{{cite journal |doi=10.1038/srep35201 |pmid=27731412 |pmc=5059667 |title=The interplay between genetic and bioelectrical signaling permits a spatial regionalisation of membrane potentials in model multicellular ensembles |journal=Scientific Reports |volume=6 |page=35201 |year=2016 |last1=Cervera |first1=Javier |last2=Meseguer |first2=Salvador |last3=Mafe |first3=Salvador |bibcode=2016NatSR...635201C }}</ref><ref name=pmid25622192>{{cite journal |doi=10.1021/jp512900x |pmid=25622192 |title=Electrical Coupling in Ensembles of Nonexcitable Cells: Modeling the Spatial Map of Single Cell Potentials |journal=The Journal of Physical Chemistry B |volume=119 |issue=7 |pages=2968–2978 |year=2015 |last1=Cervera |first1=Javier |last2=Manzanares |first2=Jose Antonio |last3=Mafe |first3=Salvador }}</ref>

Compared with the electrode-based techniques, the molecular probes provide a wider spatial resolution and facilitated dynamic analysis over time. Although calibration or titration can be possible, molecular probes are typically semi-quantitative, whereas electrodes provide absolute bioelectric values. Another advantage of [[fluorescence]] and other probes is their less-invasive nature and spatial multiplexing, enabling the simultaneous monitoring of large areas of embryonic or other tissues ''in vivo'' during normal or pathological pattering processes.<ref>{{cite journal |doi=10.1113/expphysiol.2010.053942 |pmid=20851856 |title=Optogenetic monitoring of membrane potentials |journal=Experimental Physiology |volume=96 |issue=1 |pages=13–18 |year=2011 |last1=Mutoh |first1=Hiroki |last2=Perron |first2=Amélie |last3=Akemann |first3=Walther |last4=Iwamoto |first4=Yuka |last5=Knöpfel |first5=Thomas |s2cid=5265189 |doi-access=free }}</ref>

== Roles in organisms ==

=== Early development ===

Work in model systems such as [[African clawed frog|''Xenopus laevis'']] and [[zebrafish]] has revealed a role for bioelectric signaling in the development of heart,<ref name=pmid28702127>{{cite journal |doi=10.1080/19420889.2017.1309488 |pmid=28702127 |pmc=5501196 |title=Coordinating heart morphogenesis: A novel role for hyperpolarization-activated cyclic nucleotide-gated (HCN) channels during cardiogenesis in Xenopus laevis |journal=Communicative & Integrative Biology |volume=10 |issue=3 |pages=e1309488 |year=2017 |last1=Pitcairn |first1=Emily |last2=Harris |first2=Hannah |last3=Epiney |first3=Justine |last4=Pai |first4=Vaibhav P |last5=Lemire |first5=Joan M |last6=Ye |first6=Bin |last7=Shi |first7=Nian-Qing |last8=Levin |first8=Michael |last9=McLaughlin |first9=Kelly A }}</ref><ref name=pmid28818840>{{cite journal |doi=10.1242/bio.025957 |pmid=28818840 |pmc=5665463 |title=HCN4 ion channel function is required for early events that regulate anatomical left-right patterning in a nodal and lefty asymmetric gene expression-independent manner |journal=Biology Open |volume=6 |issue=10 |pages=1445–1457 |year=2017 |last1=Pai |first1=Vaibhav P |last2=Willocq |first2=Valerie |last3=Pitcairn |first3=Emily J |last4=Lemire |first4=Joan M |last5=Paré |first5=Jean-François |last6=Shi |first6=Nian-Qing |last7=McLaughlin |first7=Kelly A |last8=Levin |first8=Michael }}</ref> face,<ref name=pmid26864374>{{cite journal |doi=10.1113/JP271930 |pmid=26864374 |pmc=4908029 |title=Bioelectric signalling via potassium channels: A mechanism for craniofacial dysmorphogenesis in KCNJ2-associated Andersen-Tawil Syndrome |journal=The Journal of Physiology |volume=594 |issue=12 |pages=3245–3270 |year=2016 |last1=Adams |first1=Dany Spencer |last2=Uzel |first2=Sebastien G. M |last3=Akagi |first3=Jin |last4=Wlodkowic |first4=Donald |last5=Andreeva |first5=Viktoria |last6=Yelick |first6=Pamela Crotty |last7=Devitt-Lee |first7=Adrian |last8=Pare |first8=Jean-Francois |last9=Levin |first9=Michael }}</ref><ref>{{cite journal |doi=10.1002/dvdy.22685 |pmid=21761475 |title=V-ATPase-dependent ectodermal voltage and ph regionalization are required for craniofacial morphogenesis |journal=Developmental Dynamics |volume=240 |issue=8 |pages=1889–1904 |year=2011 |last1=Vandenberg |first1=Laura N |last2=Morrie |first2=Ryan D |last3=Adams |first3=Dany Spencer |pmc=10277013 |s2cid=205768092 |doi-access=free }}</ref> eye,<ref name=pmid22159581/> brain,<ref name=pmid25762681>{{cite journal |doi=10.1523/JNEUROSCI.1877-14.2015 |pmid=25762681 |pmc=4355204 |title=Endogenous Gradients of Resting Potential Instructively Pattern Embryonic Neural Tissue via Notch Signaling and Regulation of Proliferation |journal=Journal of Neuroscience |volume=35 |issue=10 |pages=4366–85 |year=2015 |last1=Pai |first1=V. P |last2=Lemire |first2=J. M |last3=Pare |first3=J.-F |last4=Lin |first4=G |last5=Chen |first5=Y |last6=Levin |first6=M }}</ref><ref name=pmid26198142>{{cite journal |doi=10.1387/ijdb.150197ml |pmid=26198142 |title=Local and long-range endogenous resting potential gradients antagonistically regulate apoptosis and proliferation in the embryonic CNS |journal=The International Journal of Developmental Biology |volume=59 |issue=7–8–9 |pages=327–40 |year=2015 |last1=Pai |first1=Vaibhav P |last2=Lemire |first2=Joan M |last3=Chen |first3=Ying |last4=Lin |first4=Gufa |last5=Levin |first5=Michael |pmc=10505512 |doi-access=free }}</ref> and other organs. Screens have identified roles for ion channels in size control of structures such as the zebrafish fin,<ref name=pmid24453984>{{cite journal |doi=10.1371/journal.pgen.1004080 |pmid=24453984 |pmc=3894163 |title=Bioelectric Signaling Regulates Size in Zebrafish Fins |journal=PLOS Genetics |volume=10 |issue=1 |pages=e1004080 |year=2014 |last1=Perathoner |first1=Simon |last2=Daane |first2=Jacob M |last3=Henrion |first3=Ulrike |last4=Seebohm |first4=Guiscard |last5=Higdon |first5=Charles W |last6=Johnson |first6=Stephen L |last7=Nüsslein-Volhard |first7=Christiane |last8=Harris |first8=Matthew P |doi-access=free }}</ref> while focused gain-of-function studies have shown for example that body parts can be re-specified at the organ level – for example creating entire eyes in gut [[endoderm]].<ref name=pmid22159581/> As in the brain, developmental bioelectrics can integrate information across significant distance in the embryo, for example such as the control of brain size by bioelectric states of ventral tissue.<ref name=pmid26198142/> and the control of [[Carcinogenesis|tumorigenesis]] at the site of oncogene expression by bioelectric state of remote cells.<ref name=pmid25646081>{{cite journal |doi=10.3389/fphys.2014.00519 |pmid=25646081 |pmc=4298169 |title=Long-range gap junctional signaling controls oncogene-mediated tumorigenesis in Xenopus laevis embryos |journal=Frontiers in Physiology |volume=5 |page=519 |year=2015 |last1=Chernet |first1=Brook T |last2=Fields |first2=Chris |last3=Levin |first3=Michael |doi-access=free }}</ref><ref name=pmid24830454>{{cite journal |doi=10.18632/oncotarget.1935 |pmid=24830454 |pmc=4102810 |title=Transmembrane voltage potential of somatic cells controls oncogene-mediated tumorigenesis at long-range |journal=Oncotarget |volume=5 |issue=10 |pages=3287–306 |year=2014 |last1=Chernet |first1=Brook T |last2=Levin |first2=Michael }}</ref>

Human disorders, as well as numerous mouse mutants show that bioelectric signaling is important for human development (Tables 1 and 2). Those effects are pervasively linked to channelopathies, which are human disorders that result from mutations that disrupt ion channels.

Several [[Channelopathy|channelopathies]] result in morphological abnormalities or congenital birth defects in addition to symptoms that affect muscle and or neurons. For example, mutations that disrupt an inwardly rectifying [[potassium channel]] [[Kir2.1]] cause dominantly inherited [[Andersen–Tawil syndrome|Andersen-Tawil Syndrome]] (ATS). ATS patients experience periodic [[paralysis]], [[Heart arrhythmia|cardiac arrhythmias]], and multiple morphological abnormalities that can include [[Cleft lip and cleft palate|cleft]] or high arched palate, cleft or thin upper lip, flattened [[philtrum]], [[Micrognathism|micrognathia]], dental [[Hypodontia|oligodontia]], enamel hypoplasia, delayed dentition eruption, malocclusion, broad forehead, wide set eyes, low set ears, [[syndactyly]], [[clinodactyly]], [[brachydactyly]], and [[Dysplasia|dysplastic]] kidneys.<ref name=pmid16419128>{{cite journal |doi=10.1002/ajmg.a.31092 |pmid=16419128 |title=Andersen-Tawil syndrome: Prospective cohort analysis and expansion of the phenotype |journal=American Journal of Medical Genetics Part A |volume=140A |issue=4 |pages=312–321 |year=2006 |last1=Yoon |first1=G |last2=Oberoi |first2=S |last3=Tristani-Firouzi |first3=M |last4=Etheridge |first4=S.P |last5=Quitania |first5=L |last6=Kramer |first6=J.H |last7=Miller |first7=B.L |last8=Fu |first8=Y.H |last9=Ptáček |first9=L.J |s2cid=33899188 }}</ref><ref>{{cite journal |doi=10.1016/S0092-8674(01)00342-7 |pmid=11371347 |title=Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen's Syndrome |journal=Cell |volume=105 |issue=4 |pages=511–519 |year=2001 |last1=Plaster |first1=Nikki M |last2=Tawil |first2=Rabi |last3=Tristani-Firouzi |first3=Martin |last4=Canún |first4=Sonia |last5=Bendahhou |first5=Saı̈d |last6=Tsunoda |first6=Akiko |last7=Donaldson |first7=Matthew R |last8=Iannaccone |first8=Susan T |last9=Brunt |first9=Ewout |last10=Barohn |first10=Richard |last11=Clark |first11=John |last12=Deymeer |first12=Feza |last13=George |first13=Alfred L |last14=Fish |first14=Frank A |last15=Hahn |first15=Angelika |last16=Nitu |first16=Alexandru |last17=Ozdemir |first17=Coskun |last18=Serdaroglu |first18=Piraye |last19=Subramony |first19=S.H |last20=Wolfe |first20=Gil |last21=Fu |first21=Ying-Hui |last22=Ptáček |first22=Louis J |s2cid=17015195 |doi-access=free }}</ref> Mutations that disrupt another inwardly rectifying K<sup>+</sup> channel [[KCNJ6|Girk2]] encoded by KCNJ6 cause [[Keppen–Lubinsky syndrome|Keppen-Lubinsky syndrome]] which includes [[microcephaly]], a narrow nasal bridge, a high arched palate, and severe generalized [[lipodystrophy]] (failure to generate adipose tissue).<ref name=pmid25620207>{{cite journal |doi=10.1016/j.ajhg.2014.12.011 |pmid=25620207 |pmc=4320262 |title=Keppen-Lubinsky Syndrome is Caused by Mutations in the Inwardly Rectifying K+ Channel Encoded by KCNJ6 |journal=The American Journal of Human Genetics |volume=96 |issue=2 |pages=295–300 |year=2015 |last1=Masotti |first1=Andrea |last2=Uva |first2=Paolo |last3=Davis-Keppen |first3=Laura |last4=Basel-Vanagaite |first4=Lina |last5=Cohen |first5=Lior |last6=Pisaneschi |first6=Elisa |last7=Celluzzi |first7=Antonella |last8=Bencivenga |first8=Paola |last9=Fang |first9=Mingyan |last10=Tian |first10=Mingyu |last11=Xu |first11=Xun |last12=Cappa |first12=Marco |last13=Dallapiccola |first13=Bruno }}</ref> KCNJ6 is in the [[Down syndrome]] critical region such that duplications that include this region lead to craniofacial and limb abnormalities and duplications that do not include this region do not lead to morphological symptoms of Down syndrome.<ref>{{cite journal |doi=10.1016/j.gene.2013.11.078 |pmid=24334122 |title=A patient with partial trisomy 21 and 7q deletion expresses mild Down syndrome phenotype |journal=Gene |volume=536 |issue=2 |pages=441–443 |year=2014 |last1=Papoulidis |first1=I. |last2=Papageorgiou |first2=E. |last3=Siomou |first3=E. |last4=Oikonomidou |first4=E. |last5=Thomaidis |first5=L. |last6=Vetro |first6=A. |last7=Zuffardi |first7=O. |last8=Liehr |first8=T |last9=Manolakos |first9=E |last10=Vassilis |first10=Papadopoulos |display-authors=3 }}</ref><ref>{{cite book |doi=10.1016/S0083-6729(10)83012-2 |pmid=20831951 |chapter=Volatile Signals during Pregnancy |title=Pheromones |volume=83 |pages=289–304 |series=Vitamins & Hormones |year=2010 |last1=Vaglio |first1=Stefano |isbn=978-0-12-381516-3 }}</ref><ref>{{cite journal |doi=10.1269/jrr.09078 |pmid=19959877 |title=Pretreatment with Ascorbic Acid Prevents Lethal Gastrointestinal Syndrome in Mice Receiving a Massive Amount of Radiation |journal=Journal of Radiation Research |volume=51 |issue=2 |pages=145–156 |year=2010 |last1=Yamamoto |first1=Tetsuo |last2=Kinoshita |first2=Manabu |last3=Shinomiya |first3=Nariyoshi |last4=Hiroi |first4=Sadayuki |last5=Sugasawa |first5=Hidekazu |last6=Matsushita |first6=Yoshitaro |last7=Majima |first7=Takashi |last8=Saitoh |first8=Daizoh |last9=Seki |first9=Shuhji |display-authors=3 |bibcode=2010JRadR..51..145Y |doi-access=free }}</ref><ref>{{cite journal |doi=10.5507/bp.2013.077 |pmid=24145769 |title=Partial trisomy and tetrasomy of chromosome 21 without down syndrome phenotype and short overview of genotype-phenotype correlation. A case report |journal=Biomedical Papers |volume=158 |issue=2 |pages=321–325 |year=2013 |last1=Capkova |first1=Pavlina |last2=Misovicova |first2=Nadezda |last3=Vrbicka |first3=Dita |doi-access=free }}</ref> Mutations in [[KCNH1]], a voltage gated potassium channel lead to Temple-Baraitser (also known as [[Zimmermann–Laband syndrome|Zimmermann- Laband]]) syndrome. Common features of Temple-Baraitser syndrome include absent or hypoplastic of finger and toe nails and [[phalanges]] and joint instability. Craniofacial defects associated with mutations in KCNH1 include cleft or high arched palate, [[hypertelorism]], dysmorphic ears, dysmorphic nose, gingival hypertrophy, and abnormal number of teeth.<ref>{{cite journal |doi=10.1186/s12881-016-0304-4 |pmid=27282200 |pmc=4901505 |title=Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: One clinical entity? |journal=BMC Medical Genetics |volume=17 |issue=1 |page=42 |year=2016 |last1=Mégarbané |first1=André |last2=Al-Ali |first2=Rashid |last3=Choucair |first3=Nancy |last4=Lek |first4=Monko |last5=Wang |first5=Ena |last6=Ladjimi |first6=Moncef |last7=Rose |first7=Catherine M. |last8=Hobeika |first8=Remy |last9=MacAry |first9=Yvette |last10=Temanni |first10=Ramzi |last11=Jithesh |first11=Puthen V |last12=Chouchane |first12=Aouatef |last13=Sastry |first13=Konduru S. |last14=Thomas |first14=Remy |last15=Tomei |first15=Sara |last16=Liu |first16=Wei |last17=Marincola |first17=Francesco M. |last18=MacArthur |first18=Daniel |last19=Chouchane |first19=Lotfi |display-authors=3 |doi-access=free }}</ref><ref>{{cite journal |pmid=27267311 |year=2016 |last1=Mastrangelo |first1=M. |title=Epilepsy in KCNH1-related syndromes |journal=Epileptic Disorders |volume=18 |issue=2 |pages=123–136 |last2=Scheffer |first2=I. 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J. |last4=Durning |first4=P |last5=Maggs |first5=R |doi=10.11607/ortho.897}}</ref><ref>{{cite journal |doi=10.17796/jcpd.36.3.k854128176u764l8 |pmid=22838235 |title=Zimmermann-Laband Syndrome |journal=Journal of Clinical Pediatric Dentistry |volume=36 |issue=3 |pages=297–300 |year=2012 |last1=Sawaki |first1=K. |last2=Mishima |first2=K. |last3=Sato |first3=A. |last4=Goda |first4=Y |last5=Osugi |first5=A. |last6=Nakano |first6=M. |display-authors=3 }}</ref>{{excessive citations inline|date=November 2023}}

Mutations in [[Cav1.2|CaV1.2]], a voltage gated Ca<sup>2+</sup> channel, lead to [[Timothy syndrome]], which causes severe cardiac arrhythmia (long-QT) along with syndactyly and similar craniofacial defects to [[Andersen–Tawil syndrome|Andersen-Tawil syndrome]] including cleft or high-arched palate, micrognathia, low set ears, syndactyly and brachydactyly.<ref>{{cite journal |doi=10.1542/peds.2012-2941 |pmid=23690510 |pmc=3666110 |title=Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome |journal=Pediatrics |volume=131 |issue=6 |pages=e1991–1995 |year=2013 |last1=Dufendach |first1=K. A. |last2=Giudicessi |first2=J. R. |last3=Boczek |first3=N. J. |last4=Ackerman |first4=M. J. }}</ref><ref>{{cite journal |doi=10.1016/j.cell.2004.09.011 |pmid=15454078 |title=CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism |journal=Cell |volume=119 |issue=1 |pages=19–31 |year=2004 |last1=Splawski |first1=Igor |last2=Timothy |first2=Katherine W |last3=Sharpe |first3=Leah M |last4=Decher |first4=Niels |last5=Kumar |first5=Pradeep |last6=Bloise |first6=Raffaella |last7=Napolitano |first7=Carlo |last8=Schwartz |first8=Peter J. |last9=Joseph |first9=Robert M. |last10=Condouris |first10=Karen |last11=Tager-Flusberg |first11=Helen |last12=Priori |first12=Silvia G. |last13=Sanguinetti |first13=Michael C. |last14=Keating |first14=Mark T. |display-authors=3 |s2cid=15325633 |doi-access=free }}</ref> While these channelopathies are rare, they show that functional ion channels are important for development. Furthermore, in utero exposure to anti-epileptic medications that target some ion channels also cause increased incidence of birth defects such as oral cleft.<ref>{{cite journal |doi=10.1016/j.ajog.2012.07.008 |pmid=22917484 |pmc=3484193 |title=Use of topiramate in pregnancy and risk of oral clefts |journal=American Journal of Obstetrics and Gynecology |volume=207 |issue=5 |pages=405.e1–7 |year=2012 |last1=Margulis |first1=Andrea V. |last2=Mitchell |first2=Allen A. |last3=Gilboa |first3=Suzanne M. |last4=Werler |first4=Martha M. |last5=Mittleman |first5=Murray A |last6=Glynn |first6=Robert J. |last7=Hernandez-Diaz |first7=Sonia }}</ref><ref>{{cite journal |doi=10.1586/ern.10.57 |pmid=20518610 |pmc=2970517 |title=Teratogenic effects of antiepileptic drugs |journal=Expert Review of Neurotherapeutics |volume=10 |issue=6 |pages=943–959 |year=2014 |last1=Hill |first1=Denise S. |last2=Wlodarczyk |first2=Bogdan J. |last3=Palacios |first3=Ana M. |last4=Finnell |first4=Richard H. }}</ref><ref>{{cite book |doi=10.1016/S0074-7742(06)81006-8 |pmid=17433919 |chapter=Mechanisms of Action of Antiepileptic Drugs |title=The Neurobiology of Epilepsy and Aging |volume=81 |pages=[https://archive.org/details/neurobiologyofep0000rams/page/85 85–110] |series=International Review of Neurobiology |year=2007 |last1=White |first1=H. Steve |last2=Smith |first2=Misty D. |last3=Wilcox |first3=Karen S. |isbn=978-0-12-374018-2 |chapter-url=https://archive.org/details/neurobiologyofep0000rams/page/85 }}</ref><ref>{{cite journal |doi=10.1016/0300-483X(76)90036-6 |pmid=996878 |title=Comparative study of the teratogenicity of phenobarbitone, diphenlhydatoin and carbamazepine in mice |journal=Toxicology |volume=6 |issue=3 |pages=323–330 |year=1976 |last1=Fritz |first1=H. |last2=Müller |first2=D. |last3=Hess |first3=R. }}</ref><ref>{{cite journal |doi=10.1001/archpedi.1977.02120250071012 |pmid=412416 |title=The Fetal Trimethadione Syndrome |journal=American Journal of Diseases of Children |volume=131 |issue=12 |pages=1389–1392 |year=1977 |last1=Feldman |first1=Gerald L. |last2=Weaver |first2=D. D. |last3=Lovrien |first3=E. W. }}</ref>{{excessive citations inline|date=November 2023}} The effects of both genetic and exogenous disruption of ion channels lend insight into the importance of bioelectric signaling in development.

=== Wound healing and cell guidance ===

One of the best-understood roles for bioelectric gradients is at the tissue-level endogenous electric fields utilized during wound healing. It is challenging to study wound-associated electric fields, because these fields are weak, less fluctuating, and do not have immediate biological responses when compared to nerve pulses and muscle contraction. The development of the vibrating and glass microelectrodes, demonstrated that wounds indeed produced and, importantly, sustained measurable electric currents and electric fields.<ref name=pmid4421919/><ref name=pmid7065232>{{cite journal |doi=10.1152/ajpregu.1982.242.3.R358 |pmid=7065232 |title=The glabrous epidermis of cavies contains a powerful battery |journal=American Journal of Physiology. Regulatory, Integrative and Comparative Physiology |volume=242 |issue=3 |pages=R358–366 |year=1982 |last1=Barker |first1=A. T. |last2=Jaffe |first2=L. F. |last3=Vanable |first3=J. W. }}</ref><ref name=pmid301554/><ref name=pmid14786543>{{cite journal |doi=10.1063/1.1745444 |pmid=14786543 |title=Vibrating Probe Electrometer for the Measurement of Bioelectric Potentials |journal=Review of Scientific Instruments |volume=21 |issue=10 |pages=867–868 |year=1950 |last1=Blüh |first1=O |last2=Scott |first2=B. I. H. |bibcode=1950RScI...21..867B }}</ref><ref>{{cite journal |doi=10.1016/0014-4835(92)90164-N |pmid=1521590 |title=Electrical fields in the vicinity of epithelial wounds in the isolated bovine eye |journal=Experimental Eye Research |volume=54 |issue=6 |pages=999–1003 |year=1992 |last1=Chiang |first1=Meicheng |last2=Robinson |first2=Kenneth R. |last3=Vanable |first3=Joseph W. }}</ref><ref>{{cite journal |doi=10.1016/0012-1606(91)90239-Y |pmid=1864462 |title=Intrinsic electric fields promote epithelization of wounds in the newt, Notophthalmus viridescens |journal=Developmental Biology |volume=146 |issue=2 |pages=377–385 |year=1991 |last1=Chiang |first1=Meicheng |last2=Cragoe |first2=Edward J |last3=Vanable |first3=Joseph W }}</ref> These techniques allow further characterization of the wound electric fields/currents at cornea and skin wounds, which show active spatial and temporal features, suggesting active regulation of these electrical phenomena. For example, the wound electric currents are always the strongest at the wound edge, which gradually increased to reach a peak about 1 hour after injury.<ref name=pmid15746181>{{cite journal |doi=10.1096/fj.04-2325com |pmid=15746181 |pmc=1459277 |title=Wound healing in rat cornea: The role of electric currents |journal=The FASEB Journal |volume=19 |issue=3 |pages=379–386 |year=2005 |last1=Reid |first1=Brian |last2=Song |first2=Bing |last3=McCaig |first3=Colin D |last4=Zhao |first4=Min |doi-access=free }}</ref><ref name=pmid16871217>{{cite journal |doi=10.1038/nature04925 |pmid=16871217 |title=Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-γ and PTEN |journal=Nature |volume=442 |issue=7101 |pages=457–460 |year=2006 |last1=Zhao |first1=Min |last2=Song |first2=Bing |last3=Pu |first3=Jin |last4=Wada |first4=Teiji |last5=Reid |first5=Brian |last6=Tai |first6=Guangping |last7=Wang |first7=Fei |last8=Guo |first8=Aihua |last9=Walczysko |first9=Petr |last10=Gu |first10=Yu |last11=Sasaki |first11=Takehiko |last12=Suzuki |first12=Akira |last13=Forrester |first13=John V |last14=Bourne |first14=Henry R. |last15=Devreotes |first15=Peter N |last16=McCaig |first16=Colin D |last17=Penninger |first17=Josef M. |display-authors=3 |bibcode=2006Natur.442..457Z |s2cid=4391475 }}</ref><ref name=pmid17406628/> At wounds in [[Diabetes mellitus|diabetic]] animals, the wound electric fields are significantly compromised.<ref>{{cite journal |doi=10.1038/srep26525 |pmid=27283241 |pmc=4901296 |title=Diabetic cornea wounds produce significantly weaker electric signals that may contribute to impaired healing |journal=Scientific Reports |volume=6 |page=26525 |year=2016 |last1=Shen |first1=Yunyun |last2=Pfluger |first2=Trisha |last3=Ferreira |first3=Fernando |last4=Liang |first4=Jiebing |last5=Navedo |first5=Manuel F |last6=Zeng |first6=Qunli |last7=Reid |first7=Brian |last8=Zhao |first8=Min |bibcode=2016NatSR...626525S }}</ref> Understanding the mechanisms of generation and regulation of the wound electric currents/fields is expected to reveal new approaches to manipulate the electrical aspect for better wound healing.

How are the electric fields at a wound produced? Epithelia actively pump and differentially segregate ions. In the cornea epithelium, for example, Na<sup>+</sup> and K<sup>+</sup> are transported inwards from tear fluid to extracellular fluid, and Cl<sup>−</sup> is transported out of the extracellular fluid into the tear fluid. The epithelial cells are connected by tight junctions, forming the major electrical resistive barrier, and thus establishing an electrical gradient across the epithelium – the transepithelial potential (TEP).<ref>Maurice, D. M. The permeability to sodium ions of the living rabbit's cornea. J Physiol 112, 367-391. Pubmed Central reference number: PMC1393020</ref><ref>Klyce, S. D. Electrical profiles in the corneal epithelium. J Physiol 226, 407-429. Pubmed Central reference number: PMC1331188</ref> Breaking the epithelial barrier, as occurs in any wounds, creates a hole that breaches the high electrical resistance established by the tight junctions in the epithelial sheet, short-circuiting the epithelium locally. The TEP therefore drops to zero at the wound. However, normal ion transport continues in unwounded epithelial cells beyond the wound edge (typically <1&nbsp;mm away), driving positive charge flow out of the wound and establishing a steady, laterally-oriented electric field (EF) with the cathode at the wound. Skin also generates a TEP, and when a skin wound is made, similar wound electric currents and fields arise, until the epithelial barrier function recovers to terminate the short-circuit at the wound. When wound electric fields are manipulated with pharmacological agents that either stimulate or inhibit transport of ions, the wound electric fields also increase or decrease, respectively. Wound healing can be speed up or slowed down accordingly in cornea wounds.<ref name=pmid15746181/><ref name=pmid16871217/><ref>{{cite journal |doi=10.1242/jcs.01341 |pmid=15371524 |title=Nerve regeneration and wound healing are stimulated and directed by an endogenous electrical field in vivo |journal=Journal of Cell Science |volume=117 |issue=20 |pages=4681–4690 |year=2004 |last1=Song |first1=B |doi-access=free }}</ref>

How do electric fields affect wound healing? To heal wounds, cells surrounding the wound must migrate and grow directionally into the wound to cover the defect and restore the barrier. Cells important to heal wounds respond remarkably well to applied electric fields of the same strength that are measured at wounds. The whole gamut of cell types and their responses following injury are affected by physiological electric fields. Those include migration and division of epithelial cells, sprouting and extension of nerves, and migration of leukocytes and endothelial cells.<ref>{{cite journal |doi=10.4049/jimmunol.181.4.2465 |pmid=18684937 |pmc=2572691 |title=Lymphocyte Electrotaxis in Vitro and in Vivo |journal=The Journal of Immunology |volume=181 |issue=4 |pages=2465–2471 |year=2008 |last1=Lin |first1=F. |last2=Baldessari |first2=F. |last3=Gyenge |first3=C. C. |last4=Sato |first4=T |last5=Chambers |first5=R. D |last6=Santiago |first6=J. G. |last7=Butcher |first7=E. C. |display-authors=3 }}</ref><ref>{{cite journal |doi=10.1242/jcs.113225 |pmid=23447677 |pmc=3666251 |title=The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes |journal=Journal of Cell Science |volume=126 |issue=9 |pages=1942–1951 |year=2013 |last1=Yang |first1=H.-y |last2=Charles |first2=R.-P |last3=Hummler |first3=E |last4=Baines |first4=D. L. |last5=Isseroff |first5=R. R. }}</ref><ref>{{cite journal |doi=10.1016/j.cub.2013.02.047 |pmid=23541731 |pmc=3718648 |title=Electrophoresis of Cellular Membrane Components Creates the Directional Cue Guiding Keratocyte Galvanotaxis |journal=Current Biology |volume=23 |issue=7 |pages=560–568 |year=2013 |last1=Allen |first1=Greg M. |last2=Mogilner |first2=Alex |last3=Theriot |first3=Julie A. |bibcode=2013CBio...23..560A }}</ref><ref>{{cite journal |doi=10.1146/annurev-cellbio-100913-013357 |pmid=25062359 |title=Electrochemical Control of Cell and Tissue Polarity |journal=Annual Review of Cell and Developmental Biology |volume=30 |pages=317–336 |year=2014 |last1=Chang |first1=Fred |last2=Minc |first2=Nicolas |doi-access=free }}</ref> The most well studied cellular behavior is directional migration of epithelial cells in electric fields – [[electrotaxis]]. The epithelial cells migrate directionally to the negative pole (cathode), which at a wound is the field polarity of the endogenous vectorial electric fields in the epithelium, pointing (positive to negative) to the wound center. Epithelial cells of the cornea, keratinocytes from the skin, and many other types of cells show directional migration at electric field strengths as low as a few mV mm<sup>−1</sup>.<ref>{{cite journal |doi=10.1083/jcb.101.6.2023 |pmid=3905820 |pmc=2114002 |title=The responses of cells to electrical fields: A review |journal=The Journal of Cell Biology |volume=101 |issue=6 |pages=2023–2037 |year=1985 |last1=Robinson |first1=K. R. }}</ref><ref>{{cite journal |pmid=8834804 |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=8834804 |year=1996 |last1=Nishimura |first1=K. Y |title=Human keratinocytes migrate to the negative pole in direct current electric fields comparable to those measured in mammalian wounds |journal=Journal of Cell Science |volume=109 |issue=1 |pages=199–207 |last2=Isseroff |first2=R. R |last3=Nuccitelli |first3=R |doi=10.1242/jcs.109.1.199}}</ref><ref>{{cite journal |pmid=8799828 |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=8799828 |year=1996 |last1=Zhao |first1=M. |title=Orientation and directed migration of cultured corneal epithelial cells in small electric fields are serum dependent |journal=Journal of Cell Science |volume=109 |issue=6 |pages=1405–1414 |last2=Agius-Fernandez |first2=A. |last3=Forrester |first3=J. V. |last4=McCaig |first4=C. D. |doi=10.1242/jcs.109.6.1405}}</ref><ref>{{cite journal |doi=10.1385/CBB:33:1:33 |pmid=11322511 |title=The Galvanotaxis Response Mechanism of Keratinocytes Can Be Modeled as a Proportional Controller |journal=[[Cell Biochemistry and Biophysics]] |volume=33 |issue=1 |pages=33–51 |year=2000 |last1=Gruler |first1=Hans |last2=Nuccitelli |first2=Richard |s2cid=11731666 }}</ref> Large sheets of [[monolayer]] [[Epithelium|epithelial cells]], and sheets of stratified multilayered epithelial cells also migrate directionally.<ref name=pmid16871217/><ref>{{cite journal |pmid=8977469 |url=http://iovs.arvojournals.org/article.aspx?volume=37&page=2548 |year=1996 |last1=Zhao |first1=M |title=Directed migration of corneal epithelial sheets in physiological electric fields |journal=Investigative Ophthalmology & Visual Science |volume=37 |issue=13 |pages=2548–2558 |last2=Agius-Fernandez |first2=A |last3=Forrester |first3=J. V |last4=McCaig |first4=C. D }}</ref> Such collective movement closely resembles what happens during wound healing in vivo, where cell sheets move collectively into the wound bed to cover the wound and restore the barrier function of the skin or cornea.

How cells sense such minute extracellular electric fields remains largely elusive. Recent research has started to identify some genetic, signaling and structural elements underlying how cells sense and respond to small physiological electric fields. These include ion channels, intracellular signaling pathways, membrane lipid rafts, and electrophoresis of cellular membrane components.<ref>{{cite journal |doi=10.1038/ncomms9532 |pmid=26449415 |pmc=4603535 |title=KCNJ15/Kir4.2 couples with polyamines to sense weak extracellular electric fields in galvanotaxis |journal=Nature Communications |volume=6 |page=8532 |year=2015 |last1=Nakajima |first1=Ken-Ichi |last2=Zhu |first2=Kan |last3=Sun |first3=Yao-Hui |last4=Hegyi |first4=Bence |last5=Zeng |first5=Qunli |last6=Murphy |first6=Christopher J |last7=Small |first7=J. Victor |last8=Chen-Izu |first8=Ye |last9=Izumiya |first9=Yoshihiro |last10=Penninger |first10=Josef M |last11=Zhao |first11=Min |display-authors=3 |bibcode=2015NatCo...6.8532N }}</ref><ref>{{cite journal |doi=10.1126/scisignal.aab0562 |pmid=26012633 |pmc=4470479 |title=A large-scale screen reveals genes that mediate electrotaxis in ''Dictyostelium discoideum'' |journal=Science Signaling |volume=8 |issue=378 |pages=ra50 |year=2015 |last1=Gao |first1=Runchi |last2=Zhao |first2=Siwei |last3=Jiang |first3=Xupin |last4=Sun |first4=Yaohui |last5=Zhao |first5=Sanjun |last6=Gao |first6=Jing |last7=Borleis |first7=Jane |last8=Willard |first8=Stacey |last9=Tang |first9=Ming |last10=Cai |first10=Huaqing |last11=Kamimura |first11=Yoichiro |last12=Huang |first12=Yuesheng |last13=Jiang |first13=Jianxin |last14=Huang |first14=Zunxi |last15=Mogilner |first15=Alex |last16=Pan |first16=Tingrui |last17=Devreotes |first17=Peter N |last18=Zhao |first18=Min |display-authors=3}}</ref><ref>{{cite journal |pmid=11683396 |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=11683396 |year=2001 |last1=Djamgoz |first1=M. B. A |title=Directional movement of rat prostate cancer cells in direct-current electric field: Involvement of voltagegated Na+ channel activity |journal=Journal of Cell Science |volume=114 |issue=14 |pages=2697–2705 |last2=Mycielska |first2=M |last3=Madeja |first3=Z |last4=Fraser |first4=S. P |last5=Korohoda |first5=W |display-authors=3 |doi=10.1242/jcs.114.14.2697}}</ref><ref>{{cite journal |doi=10.1002/jcp.25259 |pmid=26580832 |pmc=4832312 |title=The Role of Kv1.2 Channel in Electrotaxis Cell Migration |journal=Journal of Cellular Physiology |volume=231 |issue=6 |pages=1375–1384 |year=2016 |last1=Zhang |first1=Gaofeng |last2=Edmundson |first2=Mathew |last3=Telezhkin |first3=Vsevolod |last4=Gu |first4=Yu |last5=Wei |first5=Xiaoqing |last6=Kemp |first6=Paul J |last7=Song |first7=Bing |display-authors=3 }}</ref><ref>{{cite journal |doi=10.1016/j.jid.2016.05.129 |pmid=27427485 |pmc=5756539 |title=Kindlin-1 Regulates Keratinocyte Electrotaxis |journal=Journal of Investigative Dermatology |volume=136 |issue=11 |pages=2229–2239 |year=2016 |last1=Zhang |first1=Gaofeng |last2=Gu |first2=Yu |last3=Begum |first3=Rumena |last4=Chen |first4=Hongduo |last5=Gao |first5=Xinghua |last6=McGrath |first6=John A |last7=Parsons |first7=Maddy |last8=Song |first8=Bing |display-authors=3 }}</ref><ref>{{cite journal |doi=10.1096/fj.01-0811fje |pmid=11967227 |title=Membrane lipids, EGF receptors, and intracellular signals colocalize and are polarized in epithelial cells moving directionally in a physiological electric field |journal=The FASEB Journal |volume=16 |issue=8 |pages=857–859 |year=2002 |last1=Zhao |first1=MIN |last2=Pu |first2=JIN |last3=Forrester |first3=John V |last4=McCaig |first4=Colin D |doi-access=free |display-authors=3 |s2cid=31682478 }}</ref><ref>{{cite journal |doi=10.1073/pnas.1702526114 |pmid=28739955 |pmc=5559012 |title=Lipid rafts sense and direct electric field-induced migration |journal=Proceedings of the National Academy of Sciences |volume=114 |issue=32 |pages=8568–8573 |year=2017 |last1=Lin |first1=Bo-Jian |last2=Tsao |first2=Shun-hao |last3=Chen |first3=Alex |last4=Hu |first4=Shu-Kai |last5=Chao |first5=Ling |last6=Chao |first6=Pen-Hsiu Grace |display-authors=3 |bibcode=2017PNAS..114.8568L |doi-access=free }}</ref>{{excessive citations inline|date=November 2023}}

=== Limb regeneration in animals ===

In the early 20th century, Albert Mathews seminally correlated regeneration of a [[cnidaria]]n polyp with the potential difference between polyp and [[stolon]] surfaces, and affected regeneration by imposing countercurrents. Amedeo Herlitzka, following on the wound electric currents footsteps of his mentor, du Bois-Raymond, theorized about electric currents playing an early role in regeneration, maybe initiating cell proliferation.<ref>{{cite book |last1=Maden |first1=M. |title=A history of regeneration research |publisher=Cambridge University |year=1991 }}{{page needed|date=May 2018}}</ref> Using electric fields overriding endogenous ones, Marsh and Beams astoundingly generated double-headed planarians and even reversed the primary body polarity entirely, with tails growing where a head previously existed.<ref>{{cite journal |doi=10.1002/jcp.1030390203 |pmid=14946235 |title=Electrical control of morphogenesis in regenerating dugesia tigrina. I. Relation of axial polarity to field strength |journal=Journal of Cellular and Comparative Physiology |volume=39 |issue=2 |pages=191–213 |year=1952 |last1=Marsh |first1=Gordon |last2=Beams |first2=H. W }}</ref> After these seed studies, variations of the idea that bioelectricity could sense injury and trigger or at least be a major player in regeneration have spurred over the decades until the present day. A potential explanation lies on resting potentials (primarily Vmem and TEP), which can be, at least in part, dormant sensors (alarms) ready to detect and effectors (triggers) ready to react to local damage.<ref name=pmid7065232/><ref>{{cite journal |doi=10.1111/j.1432-0436.1984.tb00270.x |pmid=6526168 |title=Are limb development and limb regeneration both initiated by an integumentary wounding? |journal=Differentiation |volume=28 |issue=2 |pages=87–93 |year=1984 |last1=Borgens |first1=Richard B }}</ref><ref>{{cite journal |doi=10.1111/j.1469-8986.1970.tb02232.x |pmid=5499129 |title=Square-Wave Analysis of Skin Impedance |journal=Psychophysiology |volume=7 |issue=2 |pages=262–275 |year=1970 |last1=Lykken |first1=David T }}</ref><ref name=pmid27827821/>

Following up on the relative success of electric stimulation on non-permissive frog leg regeneration using an implanted bimetallic rod in the late 1960s,<ref>{{cite journal |doi=10.1002/ar.1091580110 |pmid=6033441 |title=Induction of partial limb regeneration in ''Rana pipiens'' by galvanic stimulation |journal=The Anatomical Record |volume=158 |issue=1 |pages=89–97 |year=1967 |last1=Smith |first1=Stephen D |s2cid=22547794 }}</ref> the bioelectric extracellular aspect of amphibian limb regeneration was extensively dissected in the next decades. Definitive descriptive and functional physiological data was made possible owing to the development of the ultra-sensitive vibrating probe and improved application devices.<ref name=pmid4421919/><ref name=pmid8812127>{{cite journal |doi=10.1006/dbio.1996.0216 |pmid=8812127 |title=Reduction of the Current of Injury Leaving the Amputation Inhibits Limb Regeneration in the Red Spotted Newt |journal=Developmental Biology |volume=178 |issue=2 |pages=251–262 |year=1996 |last1=Jenkins |first1=Lisa S |last2=Duerstock |first2=Bradley S |last3=Borgens |first3=Richard B |doi-access=free }}</ref> [[Amputation]] invariably leads to a skin-driven outward current and a consequent lateral electric field setting the cathode at the wound site. Although initially pure ion leakage, an active component eventually takes place and blocking ion translocators typically impairs regeneration. Using biomimetic exogenous electric currents and fields, partial regeneration was achieved, which typically included tissue growth and increased neuronal tissue. Conversely, precluding or reverting endogenous electric current and fields impairs regeneration.<ref name=pmid301554/><ref>{{cite journal |doi=10.1073/pnas.74.10.4528 |pmid=270701 |pmc=431978 |title=Bioelectricity and regeneration: Large currents leave the stumps of regenerating newt limbs |journal=Proceedings of the National Academy of Sciences |volume=74 |issue=10 |pages=4528–32 |year=1977 |last1=Borgens |first1=R. B |last2=Vanable |first2=J. W |last3=Jaffe |first3=L. F |bibcode=1977PNAS...74.4528B |doi-access=free }}</ref><ref name=pmid8812127/><ref name="Borgens et al 1979">{{cite journal |doi=10.1002/jez.1402070206 |title=Small artificial currents enhance ''Xenopus'' limb regeneration |journal=Journal of Experimental Zoology |volume=207 |issue=2 |pages=217–226 |year=1979 |last1=Borgens |first1=Richard B |last2=Vanable |first2=Joseph W |last3=Jaffe |first3=Lionel F |bibcode=1979JEZ...207..217B }}</ref> These studies in amphibian limb regeneration and related studies in [[lamprey]]s and [[mammal]]s <ref>McCaig, C. D. Electric Fields in Vertebrate Repair.,  (The Physiological Society, 1989).</ref> combined with those of [[bone fracture]] healing<ref name=pmid4531275>{{cite journal |doi=10.1111/j.1749-6632.1974.tb26812.x |pmid=4531275 |title=Mechanical and electrical callus |journal=Annals of the New York Academy of Sciences |volume=238 |pages=457–465 |year=1974 |last1=Yasuda |first1=Iwao |s2cid=84676921 }}</ref><ref>{{cite journal |doi=10.1143/JPSJ.12.1158 |title=On the Piezoelectric Effect of Bone |journal=Journal of the Physical Society of Japan |volume=12 |issue=10 |pages=1158–1162 |year=1957 |last1=Fukada |first1=Eiichi |last2=Yasuda |first2=Iwao |bibcode=1957JPSJ...12.1158F }}</ref> and ''in vitro'' studies,<ref name=pmid16871217/> led to the general rule that migrating (such as keratinocytes, leucocytes and endothelial cells) and outgrowing (such as axons) cells contributing to regeneration undergo [[electrotaxis]] towards the cathode (injury original site). Congruently, an anode is associated with tissue resorption or degeneration, as occurs in impaired regeneration and [[osteoclast]]ic resorption in bone.<ref name=pmid4531275/><ref name="Borgens et al 1979"/><ref>Bruce M. Carlson, M. D., Ph.D. Principles of Regenerative Biology.  (Academic Press, 2007).{{page needed|date=May 2018}}</ref> Despite these efforts, the promise for a significant epimorphic regeneration in mammals remains a major frontier for future efforts, which includes the use of wearable bioreactors to provide an environment within which pro-regenerative bioelectric states can be driven<ref name=pmid27257960>{{cite journal |doi=10.1371/journal.pone.0155618 |pmid=27257960 |pmc=4892606 |title=A Tunable Silk Hydrogel Device for Studying Limb Regeneration in Adult Xenopus Laevis |journal=PLOS ONE |volume=11 |issue=6 |pages=e0155618 |year=2016 |last1=Golding |first1=Anne |last2=Guay |first2=Justin A |last3=Herrera-Rincon |first3=Celia |last4=Levin |first4=Michael |author5-link=David L. Kaplan (engineer) |last5=Kaplan |first5=David L |bibcode=2016PLoSO..1155618G |doi-access=free }}</ref><ref name=pmid20708956>{{cite journal |doi=10.1016/j.medengphy.2010.07.010 |pmid=20708956 |pmc=2967604 |title=BioDome regenerative sleeve for biochemical and biophysical stimulation of tissue regeneration |journal=Medical Engineering & Physics |volume=32 |issue=9 |pages=1065–1073 |year=2010 |last1=Hechavarria |first1=Daniel |last2=Dewilde |first2=Abiche |last3=Braunhut |first3=Susan |last4=Levin |first4=Michael |last5=Kaplan |first5=David L }}</ref> and continued efforts at electrical stimulation.<ref>{{cite journal |doi=10.1038/srep18353 |pmid=26678416 |pmc=4683620 |title=Effects of electrical stimulation on rat limb regeneration, a new look at an old model |journal=Scientific Reports |volume=5 |page=18353 |year=2015 |last1=Leppik |first1=Liudmila P |last2=Froemel |first2=Dara |last3=Slavici |first3=Andrei |last4=Ovadia |first4=Zachri N |last5=Hudak |first5=Lukasz |last6=Henrich |first6=Dirk |last7=Marzi |first7=Ingo |last8=Barker |first8=John H |bibcode=2015NatSR...518353L }}</ref>

Recent molecular work has identified proton and sodium flux as being important for tail regeneration in [[Xenopus]] tadpoles,<ref name=pmid27827821/><ref>{{cite journal |doi=10.1016/j.ydbio.2009.08.028 |pmid=19733557 |title=Electric currents in Xenopus tadpole tail regeneration |journal=Developmental Biology |volume=335 |issue=1 |pages=198–207 |year=2009 |last1=Reid |first1=Brian |last2=Song |first2=Bing |last3=Zhao |first3=Min |doi-access=free }}</ref><ref>{{cite journal |doi=10.4161/cib.22595 |pmid=23802040 |pmc=3689572 |title=Cracking the bioelectric code: Probing endogenous ionic controls of pattern formation |journal=Communicative & Integrative Biology |volume=6 |issue=1 |pages=e22595 |year=2014 |last1=Tseng |first1=Aisun |last2=Levin |first2=Michael }}</ref> and shown that regeneration of the entire tail (with spinal cord, muscle, etc.) could be triggered in a range of normally non-regenerative conditions by either molecular-genetic,<ref name=pmid17329365>{{cite journal |doi=10.1242/dev.02812 |pmid=17329365 |title=H+ pump-dependent changes in membrane voltage are an early mechanism necessary and sufficient to induce Xenopus tail regeneration |journal=Development |volume=134 |issue=7 |pages=1323–1335 |year=2007 |last1=Adams |first1=D. S |last2=Masi |first2=A |last3=Levin |first3=M |doi-access=free }}</ref> pharmacological,<ref name=pmid20881138>{{cite journal |doi=10.1523/JNEUROSCI.3315-10.2010 |pmid=20881138 |pmc=2965411 |title=Induction of Vertebrate Regeneration by a Transient Sodium Current |journal=Journal of Neuroscience |volume=30 |issue=39 |pages=13192–13200 |year=2010 |last1=Tseng |first1=A.-S |last2=Beane |first2=W. S |last3=Lemire |first3=J. M |last4=Masi |first4=A |last5=Levin |first5=M }}</ref> or optogenetic<ref name=pmid23519324>{{cite journal |doi=10.1242/bio.20133665 |pmid=23519324 |pmc=3603412 |title=Light-activation of the Archaerhodopsin H+-pump reverses age-dependent loss of vertebrate regeneration: Sparking system-level controls in vivo |journal=Biology Open |volume=2 |issue=3 |pages=306–313 |year=2013 |last1=Adams |first1=D. S |last2=Tseng |first2=A.-S |last3=Levin |first3=M }}</ref> methods. In [[planaria]], work on bioelectric mechanism has revealed control of stem cell behavior,<ref>{{cite journal |doi=10.1242/dev.006635 |pmid=17670787 |title=Smedinx-11 is a planarian stem cell gap junction gene required for regeneration and homeostasis |journal=Development |volume=134 |issue=17 |pages=3121–3131 |year=2007 |last1=Oviedo |first1=N. J |last2=Levin |first2=M |doi-access=free }}</ref> size control during remodeling,<ref>{{cite journal |doi=10.1242/dev.086900 |pmid=23250205 |pmc=3597208 |title=Bioelectric signaling regulates head and organ size during planarian regeneration |journal=Development |volume=140 |issue=2 |pages=313–322 |year=2012 |last1=Beane |first1=W. S |last2=Morokuma |first2=J |last3=Lemire |first3=J. M |last4=Levin |first4=M }}</ref> anterior-posterior polarity,<ref>{{cite journal |doi=10.1016/j.chembiol.2010.11.012 |pmid=21276941 |pmc=3278711 |title=A Chemical Genetics Approach Reveals H,K-ATPase-Mediated Membrane Voltage is Required for Planarian Head Regeneration |journal=Chemistry & Biology |volume=18 |issue=1 |pages=77–89 |year=2011 |last1=Beane |first1=Wendy S |last2=Morokuma |first2=Junji |last3=Adams |first3=Dany S |last4=Levin |first4=Michael }}</ref> and head shape.<ref name=pmid27574538/><ref name=pmid26610482>{{cite journal |doi=10.3390/ijms161126065 |pmid=26610482 |pmc=4661923 |title=Gap Junctional Blockade Stochastically Induces Different Species-Specific Head Anatomies in Genetically Wild-Type Girardia dorotocephala Flatworms |journal=International Journal of Molecular Sciences |volume=16 |issue=11 |pages=27865–27896 |year=2015 |last1=Emmons-Bell |first1=Maya |last2=Durant |first2=Fallon |last3=Hammelman |first3=Jennifer |last4=Bessonov |first4=Nicholas |last5=Volpert |first5=Vitaly |last6=Morokuma |first6=Junji |last7=Pinet |first7=Kaylinnette |last8=Adams |first8=Dany |last9=Pietak |first9=Alexis |last10=Lobo |first10=Daniel |last11=Levin |first11=Michael |doi-access=free }}</ref> Gap junction-mediated alteration of physiological signaling produces two-headed worms in Dugesia japonica; remarkably, these animals continue to regenerate as two-headed in future rounds of regeneration months after the gap junction-blocking reagent has left the tissue.<ref>{{cite journal |doi=10.1016/j.ydbio.2005.09.002 |pmid=16243308 |title=Characterization of innexin gene expression and functional roles of gap-junctional communication in planarian regeneration |journal=Developmental Biology |volume=287 |issue=2 |pages=314–335 |year=2005 |last1=Nogi |first1=Taisaku |last2=Levin |first2=Michael |doi-access=free }}</ref><ref>{{cite journal |doi=10.1016/j.ydbio.2009.12.012 |pmid=20026026 |pmc=2823934 |title=Long-range neural and gap junction protein-mediated cues control polarity during planarian regeneration |journal=Developmental Biology |volume=339 |issue=1 |pages=188–199 |year=2010 |last1=Oviedo |first1=Néstor J |last2=Morokuma |first2=Junji |last3=Walentek |first3=Peter |last4=Kema |first4=Ido P |last5=Gu |first5=Man Bock |last6=Ahn |first6=Joo-Myung |last7=Hwang |first7=Jung Shan |last8=Gojobori |first8=Takashi |last9=Levin |first9=Michael }}</ref><ref name=pmid28538159>{{cite journal |doi=10.1016/j.bpj.2017.04.011 |pmid=28538159 |pmc=5443973 |title=Long-Term, Stochastic Editing of Regenerative Anatomy via Targeting Endogenous Bioelectric Gradients |journal=Biophysical Journal |volume=112 |issue=10 |pages=2231–2243 |year=2017 |last1=Durant |first1=Fallon |last2=Morokuma |first2=Junji |last3=Fields |first3=Christopher |last4=Williams |first4=Katherine |last5=Adams |first5=Dany Spencer |last6=Levin |first6=Michael |bibcode=2017BpJ...112.2231D }}</ref> This stable, long-term alteration of the anatomical layout to which animals regenerate, without genomic editing, is an example of epigenetic inheritance of body pattern, and is also the only available "strain" of planarian species exhibiting an inherited anatomical change that is different from the wild-type.<ref>{{cite journal |doi=10.1242/bio.020149 |pmid=27565761 |pmc=5051648 |title=Vertically- and horizontally-transmitted memories – the fading boundaries between regeneration and inheritance in planaria |journal=Biology Open |volume=5 |issue=9 |pages=1177–1188 |year=2016 |last1=Neuhof |first1=Moran |last2=Levin |first2=Michael |last3=Rechavi |first3=Oded }}</ref>

[[File:Levin Figure 7.png|thumb|upright=2|Voltage changes can be transduced to downstream effector mechanisms via a variety of 2nd messenger processes, including Vmem-dependent movement of small signaling molecules like serotonin through transporters or gap junctions, voltage-sensitive phosphatases, voltage-gated calcium channels (which trigger calcium-signaling cascades), and dimerization of receptors in the cell surface.<ref name=pmid28855098/>]]

[[File:Nothing Downstream.png|thumb|upright=1.25|Bioelectricity and genetic expression work together in an integrated fashion; nothing is downstream.<ref name=pmid28633567/>]]

[[File:Misexpression of ion channels.crop.png|thumb|Misexpression of specific ion channels in diverse areas of frog embryos can induce the creation of ectopic organs, such as eyes on gut tissue.<ref name=pmid28855098/>]]

=== Cancer ===

Defection of cells from the normally tight coordination of activity towards an anatomical structure results in cancer; it is thus no surprise that bioelectricity – a key mechanism for coordinating cell growth and patterning – is a target often implicated in cancer and metastasis.<ref name=pmid23196890>{{cite journal |doi=10.1088/1478-3975/9/6/065002 |pmid=23196890 |last1=Lobikin |first1=Maria |last2=Chernet |first2=Brook |last3=Lobo |first3=Daniel |last4=Levin |first4=Michael |title=Resting potential, oncogene-induced tumorigenesis, and metastasis: the bioelectric basis of cancerin vivo |journal=Physical Biology |volume=9 |issue=6 |year=2012 |page=065002 |pmc=3528107 |bibcode=2012PhBio...9f5002L }}</ref><ref name=pmid23882223>{{cite journal |doi=10.3389/fphys.2013.00185 |pmid=23882223 |pmc=3713347 |last1=Yang |first1=Ming |last2=Brackenbury |first2=William J. |title=Membrane potential and cancer progression|journal=Frontiers in Physiology |volume=4 |year=2013 |page=185 |doi-access=free }}</ref> Indeed, it has long been known that gap junctions have a key role in carcinogenesis and progression.<ref name=pmid20446866>{{cite journal |doi=10.1517/14728222.2010.487866 |pmid=20446866 |title=Gap junctions and connexins as therapeutic targets in cancer |journal=Expert Opinion on Therapeutic Targets |volume=14 |issue=7 |pages=681–692 |year=2010 |last1=Kandouz |first1=Mustapha |last2=Batist |first2=Gerald |s2cid=30844116 }}</ref><ref name=pmid17425504>{{cite journal |doi=10.1615/CritRevOncog.v12.i3-4.30 |pmid=17425504 |title=Downregulation of Gap Junctions in Cancer Cells |journal=Critical Reviews in Oncogenesis |volume=12 |issue=3–4 |pages=225–256 |year=2006 |last1=Leithe |first1=Edward |last2=Sirnes |first2=Solveig |last3=Omori |first3=Yasufumi |last4=Rivedal |first4=Edgar }}</ref><ref name=pmid16507402>{{cite journal |doi=10.1016/S0753-3322(05)80065-4 |pmid=16507402 |title=The role of stem cells and gap junctions as targets for cancer chemoprevention and chemotherapy |journal=Biomedicine & Pharmacotherapy |volume=59 |pages=S326–331 |year=2005 |last1=Trosko |first1=J.E }}</ref> Channels can behave as oncogenes and are thus suitable as novel drug targets.<ref name=pmid26566112/><ref name=pmid26841954/><ref name=pmid20446866/><ref name=pmid24336491>{{cite journal |doi=10.1038/nrc3635 |pmid=24336491 |title=The roles of K+ channels in cancer |journal=Nature Reviews Cancer |volume=14 |issue=1 |pages=39–48 |year=2013 |last1=Pardo |first1=Luis A |last2=Stühmer |first2=Walter |s2cid=28497543 }}</ref><ref name=pmid25049269>{{cite journal |doi=10.1083/jcb.201404136 |pmid=25049269 |pmc=4107787 |title=Targeting potassium channels in cancer |journal=The Journal of Cell Biology |volume=206 |issue=2 |pages=151–162 |year=2014 |last1=Huang |first1=Xi |last2=Jan |first2=Lily Yeh }}</ref><ref name=pmid27713296>{{cite journal |doi=10.3390/ph3041202 |pmid=27713296 |pmc=4034029 |title=New Trends in Cancer Therapy: Targeting Ion Channels and Transporters |journal=Pharmaceuticals |volume=3 |issue=4 |pages=1202–1224 |year=2010 |last1=Arcangeli |first1=Annarosa |last2=Becchetti |first2=Andrea |doi-access=free }}</ref><ref name=pmid24493753>{{cite journal |doi=10.1098/rstb.2013.0105 |pmid=24493753 |pmc=3917359 |title=Regulation of voltage-gated sodium channel expression in cancer: Hormones, growth factors and auto-regulation |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=369 |issue=1638 |page=20130105 |year=2014 |last1=Fraser |first1=S. P |last2=Ozerlat-Gunduz |first2=I |last3=Brackenbury |first3=W. J |last4=Fitzgerald |first4=E. M |last5=Campbell |first5=T. M |last6=Coombes |first6=R. C |last7=Djamgoz |first7=M. B. A }}</ref><ref name=pmid24493741>{{cite journal |doi=10.1098/rstb.2013.0092 |pmid=24493741 |pmc=3917347 |title=Ion transport and cancer: From initiation to metastasis |journal=Philosophical Transactions of the Royal Society B: Biological Sciences |volume=369 |issue=1638 |page=20130092 |year=2014 |last1=Djamgoz |first1=M. B. A |last2=Coombes |first2=R. C |last3=Schwab |first3=A }}</ref><ref name=pmid23683551>{{cite journal |doi=10.1016/j.ejca.2013.03.016 |pmid=23683551 |title=Ovarian cancer: Ion channel and aquaporin expression as novel targets of clinical potential |journal=European Journal of Cancer |volume=49 |issue=10 |pages=2331–2344 |year=2013 |last1=Frede |first1=Julia |last2=Fraser |first2=Scott P |last3=Oskay-Özcelik |first3=Gülten |last4=Hong |first4=Yeosun |last5=Ioana Braicu |first5=E |last6=Sehouli |first6=Jalid |last7=Gabra |first7=Hani |last8=Djamgoz |first8=Mustafa B.A }}</ref><ref name=pmid22484465>{{cite journal |doi=10.1016/j.canlet.2012.03.036 |pmid=22484465 |title=Voltage-gated sodium channel activity promotes prostate cancer metastasis in vivo |journal=Cancer Letters |volume=323 |issue=1 |pages=58–61 |year=2012 |last1=Yildirim |first1=Senay |last2=Altun |first2=Seyhan |last3=Gumushan |first3=Hatice |last4=Patel |first4=Anup |last5=Djamgoz |first5=Mustafa B.A }}</ref>{{excessive citations inline|date=November 2023}} Recent work in amphibian models has shown that depolarization of resting potential can trigger metastatic behavior in normal cells,<ref name=pmid20959630>{{cite journal |doi=10.1242/dmm.005561 |pmid=20959630 |pmc=3008964 |title=Transmembrane potential of Gly ''Cl''-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway |journal=Disease Models & Mechanisms |volume=4 |issue=1 |pages=67–85 |year=2010 |last1=Blackiston |first1=D |last2=Adams |first2=D. S |last3=Lemire |first3=J. M |last4=Lobikin |first4=M |last5=Levin |first5=M }}</ref><ref name=pmid18931301>{{cite journal |doi=10.1073/pnas.0808328105 |jstor=25465142 |pmid=18931301 |pmc=2575467 |title=Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells |journal=Proceedings of the National Academy of Sciences |volume=105 |issue=43 |pages=16608–13 |year=2008 |last1=Morokuma |first1=J |last2=Blackiston |first2=D |last3=Adams |first3=D. S |last4=Seebohm |first4=G |last5=Trimmer |first5=B |last6=Levin |first6=M |bibcode=2008PNAS..10516608M |doi-access=free }}</ref> while hyperpolarization (induced by ion channel misexpression, drugs, or light) can suppress tumorigenesis induced by expression of human oncogenes.<ref name=pmid26988909>{{cite journal |doi=10.18632/oncotarget.8036 |pmid=26988909 |pmc=4991402 |title=Use of genetically encoded, light-gated ion translocators to control tumorigenesis |journal=Oncotarget |volume=7 |issue=15 |pages=19575–19588 |year=2016 |last1=Chernet |first1=Brook T |last2=Adams |first2=Dany S |last3=Lobikin |first3=Maria |last4=Levin |first4=Michael }}</ref> Depolarization of resting potential appears to be a bioelectric signature by which incipient tumor sites can be detected non-invasively.<ref name=pmid23471912>{{cite journal |doi=10.1242/dmm.010835 |pmid=23471912 |pmc=3634644 |title=Transmembrane voltage potential is an essential cellular parameter for the detection and control of tumor development in a Xenopus model |journal=Disease Models & Mechanisms |volume=6 |issue=3 |pages=595–607 |year=2013 |last1=Chernet |first1=B. T |last2=Levin |first2=M }}</ref> Refinement of the bioelectric signature of cancer in biomedical contexts, as a diagnostic modality, is one of the possible applications of this field.<ref name=pmid23196890/> Excitingly, the ambivalence of polarity – depolarization as marker and hyperpolarization as treatment – make it conceptually possible to derive theragnostic (portmanteau of therapeutics with diagnostics) approaches, designed to simultaneously detect and treat early tumors, in this case based on the normalization of the membrane polarization.<ref name=pmid26988909/>

=== Pattern regulation ===

Recent experiments using ion channel opener/blocker drugs, as well as dominant ion channel misexpression, in a range of model species, has shown that bioelectricity, specifically, voltage gradients instruct not only stem cell behavior<ref>{{cite journal |doi=10.1038/srep21044 |pmid=26869018 |pmc=4751571 |title=Bioelectric modulation of macrophage polarization |journal=Scientific Reports |volume=6 |page=21044 |year=2016 |last1=Li |first1=Chunmei |last2=Levin |first2=Michael |last3=Kaplan |first3=David L |bibcode=2016NatSR...621044L }}</ref><ref>{{cite journal |doi=10.1002/brb3.295 |pmid=25722947 |pmc=4321392 |title=Membrane potential depolarization causes alterations in neuron arrangement and connectivity in cocultures |journal=Brain and Behavior |volume=5 |issue=1 |pages=24–38 |year=2015 |last1=Özkucur |first1=Nurdan |last2=Quinn |first2=Kyle P |last3=Pang |first3=Jin C |last4=Du |first4=Chuang |last5=Georgakoudi |first5=Irene |last6=Miller |first6=Eric |last7=Levin |first7=Michael |last8=Kaplan |first8=David L }}</ref><ref>{{cite journal |doi=10.1387/ijdb.150198ml |pmid=26198143 |title=Selective depolarization of transmembrane potential alters muscle patterning and muscle cell localization in Xenopus laevis embryos |journal=The International Journal of Developmental Biology |volume=59 |issue=7–8–9 |pages=303–311 |year=2015 |last1=Lobikin |first1=Maria |last2=Paré |first2=Jean-François |last3=Kaplan |first3=David L |last4=Levin |first4=Michael |pmc=10461602 |doi-access=free }}</ref><ref>{{cite journal |doi=10.1016/j.biomaterials.2013.05.040 |pmid=23764116 |pmc=3724996 |title=Bioelectric modulation of wound healing in a 3D in vitro model of tissue-engineered bone |journal=Biomaterials |volume=34 |issue=28 |pages=6695–6705 |year=2013 |last1=Sundelacruz |first1=Sarah |last2=Li |first2=Chunmei |last3=Choi |first3=Young Jun |last4=Levin |first4=Michael |last5=Kaplan |first5=David L }}</ref><ref>{{cite journal |doi=10.1089/ten.tea.2012.0425.rev |pmid=23738690 |pmc=3726227 |title=Depolarization Alters Phenotype, Maintains Plasticity of Predifferentiated Mesenchymal Stem Cells |journal=Tissue Engineering Part A |volume=19 |issue=17–18 |pages=1889–1908 |year=2013 |last1=Sundelacruz |first1=Sarah |last2=Levin |first2=Michael |last3=Kaplan |first3=David L }}</ref><ref>{{cite journal |doi=10.1242/dev.011387 |pmid=18216177 |title=Initiation of human myoblast differentiation via dephosphorylation of Kir2.1 K+ channels at tyrosine 242 |journal=Development |volume=135 |issue=5 |pages=859–867 |year=2008 |last1=Hinard |first1=V |last2=Belin |first2=D |last3=Konig |first3=S |last4=Bader |first4=C. R |last5=Bernheim |first5=L |doi-access=free }}</ref>{{excessive citations inline|date=November 2023}} but also large-scale patterning.<ref name=pmid22809139/><ref>{{cite journal |doi=10.1002/bies.201100136 |pmid=22237730 |pmc=3430077 |title=Molecular bioelectricity in developmental biology: New tools and recent discoveries |journal=BioEssays |volume=34 |issue=3 |pages=205–217 |year=2012 |last1=Levin |first1=Michael }}</ref><ref>{{cite journal |doi=10.1002/wsbm.1236 |pmid=23897652 |pmc=3841289 |title=Reprogramming cells and tissue patterning via bioelectrical pathways: Molecular mechanisms and biomedical opportunities |journal=Wiley Interdisciplinary Reviews: Systems Biology and Medicine |volume=5 |issue=6 |pages=657–676 |year=2013 |last1=Levin |first1=Michael }}</ref> Patterning cues are often mediated by spatial gradients of cell resting potentials, or Vmem, which can be transduced into second messenger cascades and transcriptional changes by a handful of known mechanisms. These potentials are set by the function of ion channels and pumps, and shaped by gap junctional connections which establish developmental compartments (isopotential cell fields).<ref>{{cite journal |doi=10.1002/dneu.22405 |pmid=27265625 |title=Gap junctional signaling in pattern regulation: Physiological network connectivity instructs growth and form |journal=Developmental Neurobiology |volume=77 |issue=5 |pages=643–673 |year=2017 |last1=Mathews |first1=Juanita |last2=Levin |first2=Michael |pmc=10478170 |doi-access=free }}</ref> Because both gap junctions and ion channels are themselves voltage-sensitive, cell groups implement electric circuits with rich feedback capabilities. The outputs of developmental bioelectric dynamics ''in vivo'' represent large-scale patterning decisions such as the number of heads in planarian,<ref name=pmid28538159/> the shape of the face in frog development,<ref name=pmid26864374/> and the size of tails in zebrafish.<ref name=pmid24453984/> Experimental modulation of endogenous bioelectric prepatterns have enabled converting body regions (such as the gut) to a complete eye,<ref name=pmid22159581/> inducing regeneration of appendages such as [[tadpole]] tails at non-regenerative contexts,<ref name=pmid23519324/><ref name=pmid20881138/><ref name=pmid17329365/> and conversion of [[flatworm]] head shapes and contents to patterns appropriate to other species of flatworms, despite a normal genome.<ref name=pmid26610482/> Recent work has shown the use of physiological modeling environments for identifying predictive interventions to target bioelectric states for repair of embryonic brain defects under a range of genetic and pharmacologically induced teratologies.<ref name=pmid29519998/><ref name=pmid25762681/>

== Future research ==

Life is ultimately an electrochemical enterprise; research in this field is progressing along several frontiers. First is the reductive program of understanding how bioelectric signals are produced, how voltage changes in the cell membrane are able to regulate cell behavior, and what the genetic and epigenetic downstream targets of bioelectric signals are. A few mechanisms that transduce bioelectric change into alterations of gene expression are already known, including the bioelectric control of movement of small second-messenger molecules through cells, including serotonin and butyrate, voltage sensitive phosphatases, among others.<ref>{{cite journal |doi=10.1002/ar.22495 |pmid=22933452 |pmc=3442154 |title=Transducing Bioelectric Signals into Epigenetic Pathways During Tadpole Tail Regeneration |journal=The Anatomical Record |volume=295 |issue=10 |pages=1541–1451 |year=2012 |last1=Tseng |first1=Ai-Sun |last2=Levin |first2=Michael }}</ref><ref>{{cite journal |doi=10.1016/j.tcb.2007.04.007 |pmid=17498955 |title=Large-scale biophysics: Ion flows and regeneration |journal=Trends in Cell Biology |volume=17 |issue=6 |pages=261–270 |year=2007 |last1=Levin |first1=Michael }}</ref> Also known are numerous gene targets of voltage signaling, such as [[Notch signaling pathway|Notch]], [[BMPR1A|BMP]], [[FGF1|FGF]], and [[Hypoxia-inducible factors|HIF-1α]].<ref name=pmid14786543/> Thus, the proximal mechanisms of bioelectric signaling within single cells are becoming well-understood, and advances in [[optogenetics]]<ref name=pmid25896279/><ref name=pmid23519324/><ref name=pmid24773017/><ref>{{cite journal |doi=10.1523/JNEUROSCI.4190-10.2010 |pmid=21068304 |pmc=2997431 |title=Toward the Second Generation of Optogenetic Tools |journal=Journal of Neuroscience |volume=30 |issue=45 |pages=14998–5004 |year=2010 |last1=Knopfel |first1=T |last2=Lin |first2=M. Z |last3=Levskaya |first3=A |last4=Tian |first4=L |last5=Lin |first5=J. Y |last6=Boyden |first6=E. S }}</ref><ref>{{cite journal |doi=10.1146/annurev-neuro-061010-113817 |pmid=21692661 |title=The Development and Application of Optogenetics |journal=Annual Review of Neuroscience |volume=34 |pages=389–412 |year=2011 |last1=Fenno |first1=Lief |last2=Yizhar |first2=Ofer |last3=Deisseroth |first3=Karl |pmc=6699620 }}</ref>{{excessive citations inline|date=November 2023}} and [[magnetogenetics]]<ref>{{cite journal |doi=10.1007/s11434-015-0902-0 |pmid=26740890 |pmc=4692962 |title=Magnetogenetics: Remote non-invasive magnetic activation of neuronal activity with a magnetoreceptor |journal=Science Bulletin |volume=60 |issue=24 |pages=2107–2119 |year=2015 |last1=Long |first1=Xiaoyang |last2=Ye |first2=Jing |last3=Zhao |first3=Di |last4=Zhang |first4=Sheng-Jia |bibcode=2015SciBu..60.2107L }}</ref> continue to facilitate this research program. More challenging however is the integrative program of understanding how specific patterns of bioelectric dynamics help control the algorithms that accomplish large-scale pattern regulation (regeneration and development of complex anatomy). The incorporation of bioelectrics with chemical signaling in the emerging field of probing cell sensory perception and decision-making<ref>{{cite journal |doi=10.1016/j.molcel.2017.07.016 |pmid=28826673 |pmc=5591080 |title=Tracing Information Flow from Erk to Target Gene Induction Reveals Mechanisms of Dynamic and Combinatorial Control |journal=Molecular Cell |volume=67 |issue=5 |pages=757–769.e5 |year=2017 |last1=Wilson |first1=Maxwell Z |last2=Ravindran |first2=Pavithran T |last3=Lim |first3=Wendell A |last4=Toettcher |first4=Jared E }}</ref><ref>{{cite journal |doi=10.1083/jcb.201612094 |pmid=28003330 |pmc=5223619 |title=Interrogating cellular perception and decision making with optogenetic tools |journal=The Journal of Cell Biology |volume=216 |issue=1 |pages=25–28 |year=2017 |last1=Bugaj |first1=Lukasz J |last2=o'Donoghue |first2=Geoff P |last3=Lim |first3=Wendell A }}</ref><ref>{{cite journal |doi=10.1002/bies.201600090 |pmid=27461864 |pmc=4996742 |title=Cellular perception and misperception: Internal models for decision-making shaped by evolutionary experience |journal=BioEssays |volume=38 |issue=9 |pages=845–849 |year=2016 |last1=Mitchell |first1=Amir |last2=Lim |first2=Wendell }}</ref><ref>{{cite journal |doi=10.1126/scitranslmed.3005568 |pmid=23552369 |pmc=3772767 |title=Cell-Based Therapeutics: The Next Pillar of Medicine |journal=Science Translational Medicine |volume=5 |issue=179 |pages=179ps7 |year=2013 |last1=Fischbach |first1=M. A |last2=Bluestone |first2=J. A |last3=Lim |first3=W. A }}</ref><ref>{{cite journal |doi=10.1016/j.cell.2012.08.040 |pmid=23039994 |pmc=3498761 |title=Designing Synthetic Regulatory Networks Capable of Self-Organizing Cell Polarization |journal=Cell |volume=151 |issue=2 |pages=320–332 |year=2012 |last1=Chau |first1=Angela H |last2=Walter |first2=Jessica M |last3=Gerardin |first3=Jaline |last4=Tang |first4=Chao |last5=Lim |first5=Wendell A }}</ref><ref>{{cite journal |doi=10.1146/annurev.biophys.050708.133652 |pmid=20192780 |pmc=2965450 |title=Rewiring Cells: Synthetic Biology as a Tool to Interrogate the Organizational Principles of Living Systems |journal=Annual Review of Biophysics |volume=39 |pages=515–37 |year=2010 |last1=Bashor |first1=Caleb J |last2=Horwitz |first2=Andrew A |last3=Peisajovich |first3=Sergio G |last4=Lim |first4=Wendell A }}</ref>{{excessive citations inline|date=November 2023}} is an important frontier for future work.

Bioelectric modulation has shown control over complex morphogenesis and remodeling, not merely setting individual cell identity. Moreover, a number of the key results in this field have shown that bioelectric circuits are non-local – regions of the body make decisions based on bioelectric events at a considerable distance.<ref name=pmid25762681/><ref name=pmid25646081/><ref name=pmid24830454/> Such non-cell-autonomous events suggest distributed network models of bioelectric control;<ref>{{cite journal |doi=10.1098/rsif.2016.0555 |pmid=27807271 |pmc=5134011 |title=Top-down models in biology: Explanation and control of complex living systems above the molecular level |journal=Journal of the Royal Society Interface |volume=13 |issue=124 |page=20160555 |year=2016 |last1=Pezzulo |first1=Giovanni |last2=Levin |first2=Michael }}</ref><ref name=pmid26571046>{{cite journal |doi=10.1039/c5ib00221d |pmid=26571046 |pmc=4667987 |title=Re-membering the body: Applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs |journal=Integrative Biology |volume=7 |issue=12 |pages=1487–1517 |year=2015 |last1=Pezzulo |first1=G |last2=Levin |first2=M }}</ref><ref>{{cite journal |doi=10.1098/rsif.2014.1383 |pmid=25788538 |pmc=4387527 |title=Knowing one's place: A free-energy approach to pattern regulation |journal=Journal of the Royal Society Interface |volume=12 |issue=105 |page=20141383 |year=2015 |last1=Friston |first1=K |last2=Levin |first2=M |last3=Sengupta |first3=B |last4=Pezzulo |first4=G }}</ref> new computational and conceptual paradigms may need to be developed to understand spatial information processing in bioelectrically active tissues. It has been suggested that results from the fields of primitive cognition and unconventional computation are relevant<ref name=pmid26571046/><ref>{{cite journal |doi=10.1113/jphysiol.2014.271940 |pmid=24882814 |pmc=4048089 |title=Endogenous bioelectrical networks store non-genetic patterning information during development and regeneration |journal=The Journal of Physiology |volume=592 |issue=11 |pages=2295–2305 |year=2014 |last1=Levin |first1=Michael }}</ref><ref name=pmid27574538/> to the program of cracking the bioelectric code. Finally, efforts in biomedicine and bioengineering are developing applications such as wearable bioreactors for delivering voltage-modifying reagents to wound sites,<ref name=pmid20708956/><ref name=pmid27257960/> and ion channel-modifying drugs (a kind of electroceutical) for repair of birth defects<ref name=pmid29519998/> and regenerative repair.<ref name=pmid20881138/> Synthetic biologists are likewise starting to incorporate bioelectric circuits into hybrid constructs.<ref>{{cite journal |doi=10.1103/PhysRevX.6.031001 |title=Optically Controlled Oscillators in an Engineered Bioelectric Tissue |journal=Physical Review X |volume=6 |issue=3 |year=2016 |last1=McNamara |first1=Harold M |last2=Zhang |first2=Hongkang |last3=Werley |first3=Christopher A |last4=Cohen |first4=Adam E |page=031001 |bibcode=2016PhRvX...6c1001M |doi-access=free }}</ref>

'''Table 1:''' Ion Channels and Pumps Implicated in Patterning

{| class="wikitable" |-
!Protein
!Morphogenetic role or LOF (loss of function) phenotype
!Species
!Reference
|-
|TRH1 K<sup>+</sup> transporter
|Root hair patterning
|''Arabidopsis''
|<ref>{{cite journal |pmid=11158535 |pmc=102205 |year=2001 |last1=Rigas |first1=S |title=TRH1 encodes a potassium transporter required for tip growth in Arabidopsis root hairs |journal=The Plant Cell |volume=13 |issue=1 |pages=139–151 |last2=Debrosses |first2=G |last3=Haralampidis |first3=K |last4=Vicente-Agullo |first4=F |last5=Feldmann |first5=K. A |last6=Grabov |first6=A |last7=Dolan |first7=L |last8=Hatzopoulos |first8=P |doi=10.1105/tpc.13.1.139}}</ref>
|-
|Kir2.1potassium channel
|Wing patterning
|''Drosophila''
|<ref name="ReferenceB">{{cite journal |pmid=22949619 |pmc=3436115 |year=2012 |last1=Dahal |first1=G. R |title=An inwardly rectifying K+ channel is required for patterning |journal=Development |volume=139 |issue=19 |pages=3653–3664 |last2=Rawson |first2=J |last3=Gassaway |first3=B |last4=Kwok |first4=B |last5=Tong |first5=Y |last6=Ptácek |first6=L. J |last7=Bates |first7=E |doi=10.1242/dev.078592 }}</ref>
|-
|Kir7.1 K<sup>+</sup> channel
|Craniofacial patterning, lung development
|''Mus musculus''
|<ref>{{cite journal |pmid=26402555 |pmc=4581704 |year=2015 |last1=Villanueva |first1=S |title=Cleft Palate, Moderate Lung Developmental Retardation and Early Postnatal Lethality in Mice Deficient in the Kir7.1 Inwardly Rectifying K+ Channel |journal=PLOS ONE |volume=10 |issue=9 |pages=e0139284 |last2=Burgos |first2=J. |last3=López-Cayuqueo |first3=K. I. |last4=Lai |first4=K. M. |last5=Valenzuela |first5=D. M. |last6=Cid |first6=L. P. |last7=Sepúlveda |first7=F. V. |display-authors=3 |doi=10.1371/journal.pone.0139284 |bibcode=2015PLoSO..1039284V |doi-access=free }}</ref>
|-
|NHE2 Na<sup>+</sup>/H<sup>+</sup> exchanger
|Epithelial patterning
|''Drosophila''
|<ref>{{cite journal |pmid=19234454 |pmc=2803043 |year=2009 |last1=Simons |first1=M |title=Electrochemical cues regulate assembly of the Frizzled/Dishevelled complex at the plasma membrane during planar epithelial polarization |journal=Nature Cell Biology |volume=11 |issue=3 |pages=286–294 |last2=Gault |first2=W. J. |last3=Gotthardt |first3=D. |last4=Rohatgi |first4=R |last5=Klein |first5=T. J. |last6=Shao |first6=Y |last7=Lee |first7=H. J. |last8=Wu |first8=A. L. |last9=Fang |first9=Y |last10=Satlin |first10=L. M. |last11=Dow |first11=J. T. |last12=Chen |first12=J |last13=Zheng |first13=J |last14=Boutros |first14=M. |last15=Mlodzik |first15=M. |display-authors=3 |doi=10.1038/ncb1836 }}</ref>
|-
|V-ATPase proton pump
|Wing hair patterning, Pigmentation and brain patterning, Craniofacial patterning
|''Drosophila, Oryzias latipes, Homo sapiens''
|<ref>{{cite journal |pmid=20579879 |year=2010 |last1=Hermle |first1=T |title=Regulation of Frizzled-dependent planar polarity signaling by a V-ATPase subunit |journal=Current Biology |volume=20 |issue=14 |pages=1269–1276 |last2=Saltukoglu |first2=D. |last3=Grünewald |first3=J. |last4=Walz |first4=G. |last5=Simons |first5=M. |display-authors=3 |doi=10.1016/j.cub.2010.05.057 |s2cid=15407237 |doi-access=free |bibcode=2010CBio...20.1269H }}</ref><ref>{{cite journal |pmid=24225653 |pmc=3827601 |year=2013 |last1=Müller |first1=C. |title=The medaka mutation tintachina sheds light on the evolution of V-ATPase B subunits in vertebrates |journal=Scientific Reports |volume=3 |page=3217 |last2=Maeso |first2=I |last3=Wittbrodt |first3=J. |last4=Martínez-Morales |first4=J. R. |doi=10.1038/srep03217 |bibcode=2013NatSR...3E3217M }}</ref><ref>{{cite journal |pmid=12566520 |pmc=1735376 |year=2003 |last1=Borthwick |first1=K. J. |title=A phenocopy of CAII deficiency: A novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis |journal=Journal of Medical Genetics |volume=40 |issue=2 |pages=115–121 |last2=Kandemir |first2=N. |last3=Topaloglu |first3=R. |last4=Kornak |first4=U. |last5=Bakkaloglu |first5=A. |last6=Yordam |first6=N |last7=Ozen |first7=S. |last8=Mocan |first8=H. |last9=Shah |first9=G. N. |last10=Sly |first10=W. S. |last11=Karet |first11=F. E. |display-authors=3 |doi=10.1136/jmg.40.2.115}}</ref>
|-
|HCN1, Kv3.1 K<sup>+</sup> channels
|Forebrain patterning
|''Mus musculus''
|<ref name=pmid26216856>{{cite journal |doi=10.1085/jgp.201511461 |pmid=26216856 |pmc=4516783 |title=A new standard: A review of ''Handbook'' of Ion Channels |journal=The Journal of General Physiology |volume=146 |issue=2 |pages=119–121 |year=2015 |last1=Aldrich |first1=Richard W. }}</ref><ref>{{cite journal |pmid=23821603 |pmc=3829632 |year=2013 |last1=Duque |first1=A. |title=Expression of Kv1.3 potassium channels regulates density of cortical interneurons |journal=Developmental Neurobiology |volume=73 |issue=11 |pages=841–855 |last2=Gazula |first2=V. R. |last3=Kaczmarek |first3=L. K. |doi=10.1002/dneu.22105 }}</ref>
|-
|KCNC1 K<sup>+</sup> channel
|Growth deficits
|''Mus musculus''
|<ref>Zheng, J. a. T., M. C. Handbook of ion channels.  (CRC Press, 2015).{{page needed|date=May 2018}}</ref>
|-
|TWIK-1 K<sup>+</sup> channel (KCNK1)
|Cardiac (atrial) size
|''Mus musculus''
|<ref>{{cite journal |pmid=27103460 |year=2016 |last1=Christensen |first1=A. H |title=The two-pore domain potassium channel, TWIK-1, has a role in the regulation of heart rate and atrial size |journal=Journal of Molecular and Cellular Cardiology |volume=97 |pages=24–35 |last2=Chatelain |first2=F. C. |last3=Huttner |first3=I. G. |last4=Olesen |first4=M. S. |last5=Soka |first5=M. |last6=Feliciangeli |first6=S |last7=Horvat |first7=C |last8=Santiago |first8=C. F. |last9=Vandenberg |first9=J. I |last10=Schmitt |first10=N. |last11=Olesen |first11=S. P. |last12=Lesage |first12=F. |last13=Fatkin |first13=D. |display-authors=3 |doi=10.1016/j.yjmcc.2016.04.006 }}</ref>
|-
|KCNJ6 K<sup>+</sup>channel
|Keppen-Lubinsky syndrome – craniofacial and brain
|''Homo sapiens''
|<ref name=pmid25620207 />
|-
|KCNH1 (hEAG1) K<sup>+</sup> channel and ATP6V1B2 V-ATPase proton pump
|Zimmermman-Laband and Temple-Baraitser syndrome – craniofacial and brain defects, dysplasia/aplasia of nails of thumb and great toe.
|''Homo sapiens''
|<ref name=pmid25915598 /><ref>{{cite journal |pmid=25420144 |year=2015 |last1=Simons |first1=C |title=Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy |journal=Nature Genetics |volume=47 |issue=1 |pages=73–77 |last2=Rash |first2=L. D. |last3=Crawford |first3=J |last4=Ma |first4=L |last5=Cristofori-Armstrong |first5=B. |last6=Miller |first6=D |last7=Ru |first7=K. |last8=Baillie |first8=G. J |last9=Alanay |first9=Y. |last10=Jacquinet |first10=A. |last11=Debray |first11=F. G. |last12=Verloes |first12=A |last13=Shen |first13=J. |last14=Yesil |first14=G. |last15=Guler |first15=S. |last16=Yuksel |first16=A. |last17=Cleary |first17=J. G. |last18=Grimmond |first18=S. M. |last19=McGaughran |first19=J. |last20=King |first20=G. F. |last21=Gabbett |first21=M. T |last22=Taft |first22=R. J. |display-authors=3 |doi=10.1038/ng.3153 |s2cid=52799681 }}</ref>
|-
|GLRa4 chloride channel
|Craniofacial anomalies
|''Homo sapiens''
|<ref>{{cite journal |pmid=27506666 |pmc=4979147 |year=2016 |last1=Labonne |first1=J. D. |title=A microdeletion at Xq22.2 implicates a glycine receptor GLRA4 involved in intellectual disability, behavioral problems and craniofacial anomalies |journal=BMC Neurology |volume=16 |page=132 |last2=Graves |first2=T. D. |last3=Shen |first3=Y. |last4=Jones |first4=J. R. |last5=Kong |first5=I. K. |last6=Layman |first6=L. C. |last7=Kim |first7=H. G. |display-authors=3 |doi=10.1186/s12883-016-0642-z |doi-access=free }}</ref>
|-
|KCNJ8 K<sup>+</sup>
|Cantu syndrome – face, heart, skeleton, brain defects
|''Homo sapiens''
|<ref>{{cite journal |pmid=24352916 |year=2014 |last1=Hiraki |first1=Y. |title=Aortic aneurysm and craniosynostosis in a family with Cantu syndrome |journal=American Journal of Medical Genetics Part A |volume=164A |issue=1 |pages=231–236 |last2=Miyatake |first2=S. |last3=Hayashidani |first3=M. |last4=Nishimura |first4=Y. |last5=Matsuura |first5=H. |last6=Kamada |first6=M. |last7=Kawagoe |first7=T. |last8=Yunoki |first8=K. |last9=Okamoto |first9=N |last10=Yofune |first10=H |last11=Nakashima |first11=M. |last12=Tsurusaki |first12=Y. |last13=Satisu |first13=H |last14=Murakami |first14=A |last15=Miyake |first15=N. |last16=Nishimura |first16=G. |last17=Matsumoto |first17=N. |display-authors=3 |doi=10.1002/ajmg.a.36228 |s2cid=73121 }}</ref><ref>{{cite journal |pmid=24700710 |pmc=4277879 |year=2014 |last1=Cooper |first1=P. E |title=Cantú syndrome resulting from activating mutation in the KCNJ8 gene |journal=Human Mutation |volume=35 |issue=7 |pages=809–813 |last2=Reutter |first2=H. |last3=Woelfle |first3=J. |last4=Engels |first4=H. |last5=Grange |first5=D. K |last6=Van Haaften |first6=G |last7=Van Bon |first7=B. W |last8=Hoischen |first8=A. |last9=Nichols |first9=C. G. |display-authors=3 |doi=10.1002/humu.22555 }}</ref><ref>{{cite journal |pmid=24176758 |pmc=3902017 |year=2013 |last1=Brownstein |first1=C. A. |title=Mutation of KCNJ8 in a patient with Cantú syndrome with unique vascular abnormalities - support for the role of K(ATP) channels in this condition |journal=European Journal of Medical Genetics |volume=56 |issue=12 |pages=678–682 |last2=Towne |first2=M. C. |last3=Luquette |first3=L. J |last4=Harris |first4=D. J |last5=Marinakis |first5=N. S |last6=Meinecke |first6=P |last7=Kutsche |first7=K. |last8=Campeau |first8=P. M |last9=Yu |first9=T. W. |last10=Margulies |first10=D. M. |last11=Agrawal |first11=P. B. |last12=Beggs |first12=A. H. |display-authors=3 |doi=10.1016/j.ejmg.2013.09.009 }}</ref>
|-
|NALCN (Na<sup>+</sup> leak channel)
|Freeman-Sheldon syndrome – limbs, face, brain
|''Homo sapiens''
|<ref>{{cite journal |pmid=25683120 |pmc=4375444 |year=2015 |last1=Chong |first1=J. X. |title=De novo mutations in NALCN cause a syndrome characterized by congenital contractures of the limbs and face, hypotonia, and developmental delay |journal=The American Journal of Human Genetics |volume=96 |issue=3 |pages=462–473 |last2=McMillin |first2=M. J. |last3=Shively |first3=K. M. |last4=Beck |first4=A. E. |last5=Marvin |first5=C. T. |last6=Armenteros |first6=J. R. |last7=Buckingham |first7=K. J. |last8=Nkinsi |first8=N. T. |last9=Boyle |first9=E. A |last10=Berry |first10=M. N. |last11=Bocian |first11=M. |last12=Foulds |first12=N. |last13=Uzielli |first13=M. L. |last14=Haldeman-Englert |first14=C. |last15=Hennekam |first15=R. C. |last16=Kaplan |first16=P |last17=Kline |first17=A. D. |last18=Mercer |first18=C. L. |last19=Nowaczyk |first19=M. J. |last20=Klein Wassink-Ruiter |first20=J. S |last21=McPherson |first21=E. W |last22=Moreno |first22=R. A. |last23=Scheuerle |first23=A. E |last24=Shashi |first24=V |last25=Stevens |first25=C. A |last26=Carey |first26=J. C. |last27=Monteil |first27=A |last28=Lory |first28=P |last29=Tabor |first29=H. K. |last30=Smith |first30=J. D. |display-authors=3 |doi=10.1016/j.ajhg.2015.01.003 }}</ref>
|-
|CFTR chloride channel
|Bilateral absence of vas deferens
|''Homo sapiens''
|<ref>{{cite journal |pmid=16272798 |year=2005 |last1=Uzun |first1=S |title=Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens |journal=The Tohoku Journal of Experimental Medicine |volume=207 |issue=4 |pages=279–285 |last2=Gökçe |first2=S. |last3=Wagner |first3=K. |doi=10.1620/tjem.207.279 |doi-access=free }}</ref><ref>{{cite journal |pmid=16840743 |pmc=2648063 |year=2006 |last1=Wilschanski |first1=M. |title=Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials |journal=American Journal of Respiratory and Critical Care Medicine |volume=174 |issue=7 |pages=787–794 |last2=Dupuis |first2=A. |last3=Ellis |first3=L. |last4=Jarvi |first4=K. |last5=Zielenski |first5=J. |last6=Tullis |first6=E. |last7=Martin |first7=S. |last8=Corey |first8=M |last9=Tsui |first9=L. C. |last10=Durie |first10=P. |display-authors=3 |doi=10.1164/rccm.200509-1377OC }}</ref>
|-
|KCNC1
|Head/face dysmorphias
|''Homo sapiens''
|<ref>{{cite journal |pmid=28145425 |pmc=5437909 |year=2017 |last1=Poirier |first1=K. |title=Loss of Function of KCNC1 is associated with intellectual disability without seizures |journal=European Journal of Human Genetics |volume=25 |issue=5 |pages=560–564 |last2=Viot |first2=G. |last3=Lombardi |first3=L. |last4=Jauny |first4=C. |last5=Billuart |first5=P. |last6=Bienvenu |first6=T. |doi=10.1038/ejhg.2017.3 }}</ref>
|-
|KCNK9, TASK3 K<sup>+</sup> channels
|Birk-Barel Dysmorphism Syndrome – craniofacial defects, brain (cortical patterning) defects
|''Homo sapiens''
|<ref>{{cite journal |pmid=24342771 |year=2014 |last1=Veale |first1=E. L |title=Recovery of current through mutated TASK3 potassium channels underlying Birk Barel syndrome |journal=Molecular Pharmacology |volume=85 |issue=3 |pages=397–407 |last2=Hassan |first2=M. |last3=Walsh |first3=Y. |last4=Al-Moubarak |first4=E. |last5=Mathie |first5=A. |display-authors=3 |doi=10.1124/mol.113.090530 |s2cid=14790826 }}</ref><ref>{{cite journal |pmid=18678320 |pmc=2495061 |year=2008 |last1=Barel |first1=O |title=Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9 |journal=The American Journal of Human Genetics |volume=83 |issue=2 |pages=193–199 |last2=Shalev |first2=S. A. |last3=Ofir |first3=R. |last4=Cohen |first4=A |last5=Zlotogora |first5=J |last6=Shorer |first6=Z. |last7=Mazor |first7=G. |last8=Finer |first8=G |last9=Khateeb |first9=S |last10=Zilberberg |first10=N |last11=Birk |first11=O. S. |display-authors=3 |doi=10.1016/j.ajhg.2008.07.010 }}</ref><ref name=pmid15115830>{{cite journal |doi=10.1056/NEJMoa032922 |pmid=15115830 |title=Activating Mutations in the Gene Encoding the ATP-Sensitive Potassium-Channel Subunit Kir6.2 and Permanent Neonatal Diabetes |journal=New England Journal of Medicine |volume=350 |issue=18 |pages=1838–1849 |year=2004 |last1=Gloyn |first1=Anna L |last2=Pearson |first2=Ewan R |last3=Antcliff |first3=Jennifer F. |last4=Proks |first4=Peter |last5=Bruining |first5=G. Jan |last6=Slingerland |first6=Annabelle S |last7=Howard |first7=Neville |last8=Srinivasan |first8=Shubha |last9=Silva |first9=José M. C. L. |last10=Molnes |first10=Janne |last11=Edghill |first11=Emma L |last12=Frayling |first12=Timothy M. |last13=Temple |first13=I. Karen |last14=MacKay |first14=Deborah |last15=Shield |first15=Julian P. H. |last16=Sumnik |first16=Zdenek |last17=Van Rhijn |first17=Adrian |last18=Wales |first18=Jerry K. H. |last19=Clark |first19=Penelope |last20=Gorman |first20=Shaun |last21=Aisenberg |first21=Javier |last22=Ellard |first22=Sian |last23=Njølstad |first23=Pål R. |last24=Ashcroft |first24=Frances M. |last25=Hattersley |first25=Andrew T. |display-authors=3 |url=https://espace.library.uq.edu.au/view/UQ:369557/UQ369557_OA.pdf }}</ref>
|-
|Kir6.2 K<sup>+</sup> channel
|Craniofacial defects
|''Homo sapiens''
|<ref name=pmid15115830/>
|-
|KCNQ1 K<sup>+</sup> channel (via epigenetic regulation)
|Hypertrophy of tongue, liver, spleen, pancreas, kidneys, adrenals, genitalia – Beckwith-Wiedemann syndrome; craniofacial and limb defects, early development
|''Homo sapiens, Mus musculus, Drosophila''
|<ref>{{cite journal |pmid=11120752 |pmc=387258 |year=2000 |last1=Lee |first1=M. P. |title=Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice |journal=Journal of Clinical Investigation |volume=106 |issue=12 |pages=1447–1455 |last2=Ravenel |first2=J. D. |last3=Hu |first3=R. J. |last4=Lustig |first4=L. R. |last5=Tomaselli |first5=G |last6=Berger |first6=R. D |last7=Brandenburg |first7=S. A. |last8=Litzi |first8=T. J. |last9=Bunton |first9=T. E. |last10=Limb |first10=C |last11=Francis |first11=H |last12=Gorelikow |first12=M |last13=Gu |first13=H |last14=Washington |first14=K |last15=Argani |first15=P |last16=Goldenring |first16=J. R. |last17=Coffey |first17=R. J |last18=Feinberg |first18=A. P. |display-authors=3|doi=10.1172/JCI10897 }}</ref><ref name=pmid11751681>{{cite journal |pmid=11751681 |year=2001 |last1=Weksberg |first1=R |title=Tumor development in the Beckwith-Wiedemann syndrome is associated with a variety of constitutional molecular 11p15 alterations including imprinting defects of KCNQ1OT1 |journal=Human Molecular Genetics |volume=10 |issue=26 |pages=2989–3000 |last2=Nishikawa |first2=J. |last3=Caluseriu |first3=O. |last4=Fei |first4=Y. L |last5=Shuman |first5=C. |last6=Wei |first6=C. |last7=Steele |first7=L. |last8=Cameron |first8=J. |last9=Smith |first9=A. |last10=Ambus |first10=I. |last11=Li |first11=M. |last12=Ray |first12=P. N. |last13=Sadowski |first13=P. |last14=Squire |first14=J. |display-authors=3 |doi=10.1093/hmg/10.26.2989|doi-access=free }}</ref><ref>{{cite journal |pmid=10710224 |year=2000 |last1=Moore |first1=E. S. |title=Heterogeneity in Wiedemann-Beckwith syndrome: Anthropometric evidence |journal=American Journal of Medical Genetics |volume=90 |issue=4 |pages=283–290 |last2=Ward |first2=R. E |last3=Escobar |first3=L. F. |last4=Carlin |first4=M. E. |doi=10.1002/(SICI)1096-8628(20000214)90:4<283::AID-AJMG4>3.0.CO;2-F }}</ref><ref>{{cite journal |pmid=16267222 |year=2005 |last1=Wen |first1=H. |title=A Drosophila KCNQ channel essential for early embryonic development |journal=Journal of Neuroscience |volume=25 |issue=44 |pages=10147–10156 |last2=Weiger |first2=T. M. |last3=Ferguson |first3=T. S. |last4=Shahidullah |first4=M. |last5=Scott |first5=S. S. |last6=Levitan |first6=I. B. |display-authors=3 |doi=10.1523/JNEUROSCI.3086-05.2005 |pmc=6725806 |doi-access=free }}</ref>
|-
|KCNQ1 K<sup>+</sup> channel
|Jervell and Lange-Nielsen syndrome - inner ear and limb
|''Homo sapiens, Mus musculus''
|<ref>{{cite journal |pmid=15891643 |year=2005 |last1=Rivas |first1=A |title=Inner ear abnormalities in a Kcnq1 (Kvlqt1) knockout mouse: A model of Jervell and Lange-Nielsen syndrome |journal=Otology & Neurotology |volume=26 |issue=3 |pages=415–424 |last2=Francis |first2=H. W |doi=10.1097/01.mao.0000169764.00798.84|s2cid=1700736 }}</ref><ref>{{cite journal |pmid=15498462 |year=2004 |last1=Casimiro |first1=M. C |title=Targeted point mutagenesis of mouse Kcnq1: Phenotypic analysis of mice with point mutations that cause Romano-Ward syndrome in humans |journal=Genomics |volume=84 |issue=3 |pages=555–564 |last2=Knollmann |first2=B. C |last3=Yamoah |first3=E. N |last4=Nie |first4=L |last5=Vary Jr |first5=J. C |last6=Sirenko |first6=S. G |last7=Greene |first7=A. E |last8=Grinberg |first8=A |last9=Huang |first9=S. P |last10=Ebert |first10=S. N |last11=Pfeifer |first11=K |doi=10.1016/j.ygeno.2004.06.007 }}</ref><ref>{{cite journal |pmid=9312006 |pmc=1170178 |year=1997 |last1=Chouabe |first1=C |title=Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias |journal=The EMBO Journal |volume=16 |issue=17 |pages=5472–5479 |last2=Neyroud |first2=N |last3=Guicheney |first3=P |last4=Lazdunski |first4=M. |last5=Romey |first5=G. |last6=Barhanin |first6=J. |display-authors=3 |doi=10.1093/emboj/16.17.5472 }}</ref>
|-
|Kir2.1 K<sup>+</sup> channel (KNCJ2)
|Andersen-Tawil syndrome – craniofacial, limb, ribs
|''Homo sapiens, Mus musculus''
|<ref name=pmid16419128/><ref name="ReferenceB"/><ref>{{cite journal |pmid=14522976 |year=2003 |last1=Bendahhou |first1=S |title=Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome |journal=Journal of Biological Chemistry |volume=278 |issue=51 |pages=51779–51785 |last2=Donaldson |first2=M. R |last3=Plaster |first3=N. M |last4=Tristani-Firouzi |first4=M |last5=Fu |first5=Y. H |last6=Ptácek |first6=L. J. |display-authors=3 |doi=10.1074/jbc.M310278200 |doi-access=free }}</ref>
|-
|GABA-A receptor (chloride channel)
|Angelman Syndrome - craniofacial (e.g., cleft palate) and hand patterning
|''Homo sapiens, Mus musculus''
|<ref>{{cite journal |pmid=7581464 |year=1995 |last1=Culiat |first1=C. T .|title=Deficiency of the beta 3 subunit of the type a gamma-aminobutyric acid receptor causes cleft palate in mice |journal=Nature Genetics |volume=11 |issue=3 |pages=344–346 |last2=Stubbs |first2=L. J. |last3=Woychik |first3=R. P |last4=Russell |first4=L. B. |last5=Johnson |first5=D. K. |last6=Rinchik |first6=E. M. |doi=10.1038/ng1195-344 |s2cid=19397785 }}</ref><ref>{{cite journal |pmid=4088436 |year=1985 |last1=Wee |first1=E. L |title=GABA uptake in embryonic palate mesenchymal cells of two mouse strains |journal=Neurochemical Research |volume=10 |issue=12 |pages=1673–1688 |last2=Zimmerman |first2=E. F |doi=10.1007/bf00988609|s2cid=26049392 }}</ref><ref>{{cite journal |pmid=9108119 |pmc=20582 |year=1997 |last1=Homanics |first1=G. E |title=Mice devoid of gamma-aminobutyrate type a receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=94 |issue=8 |pages=4143–4148 |last2=Delorey |first2=T. M. |last3=Firestone |first3=L. L. |last4=Quinlan |first4=J. J |last5=Handforth |first5=A. |last6=Harrison |first6=N. L. |last7=Krasowski |first7=M. D. |last8=Rick |first8=C. E |last9=Korpi |first9=E. R. |last10=Mäkelä |first10=R. |last11=Brilliant |first11=M. H. |last12=Hagiwara |first12=N |last13=Ferguson |first13=C |last14=Snyder |first14=K. |last15=Olsen |first15=R. W. |display-authors=3 |doi=10.1073/pnas.94.8.4143 |bibcode=1997PNAS...94.4143H |doi-access=free }}</ref>
|-
|TMEM16A chloride channel
|Tracheal morphogenesis
|''Mus musculus''
|<ref>{{cite journal |pmid=18585372 |year=2008 |last1=Rock |first1=J. R. |title=The transmembrane protein TMEM16A is required for normal development of the murine trachea |journal=Developmental Biology |volume=321 |issue=1 |pages=141–149 |last2=Futtner |first2=C. R. |last3=Harfe |first3=B. D. |doi=10.1016/j.ydbio.2008.06.009 |doi-access=free }}</ref>
|-
|Girk2 K<sup>+</sup> channel
|Cerebellar development defects
|''Mus musculus''
|<ref>{{cite journal |pmid=4128371 |year=1973 |last1=Rakic |first1=P |title=Sequence of developmental abnormalities leading to granule cell deficit in cerebellar cortex of weaver mutant mice |journal=The Journal of Comparative Neurology |volume=152 |issue=2 |pages=103–132 |last2=Sidman |first2=R. L. |doi=10.1002/cne.901520202 |s2cid=6553698 }}</ref><ref>{{cite journal |pmid=4509657 |pmc=433223 |year=1973 |last1=Rakic |first1=P |title=Weaver mutant mouse cerebellum: Defective neuronal migration secondary to abnormality of Bergmann glia |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=70 |issue=1 |pages=240–244 |last2=Sidman |first2=R. L |doi=10.1073/pnas.70.1.240|bibcode=1973PNAS...70..240R |doi-access=free }}</ref><ref>{{cite journal |pmid=3528411 |year=1986 |last1=Hatten |first1=M. E |title=Weaver mouse cerebellar granule neurons fail to migrate on wild-type astroglial processes in vitro |journal=The Journal of Neuroscience |volume=6 |issue=9 |pages=2676–2683 |last2=Liem |first2=R. K |last3=Mason |first3=C. A |doi=10.1523/jneurosci.06-09-02676.1986|pmc=6568692|doi-access=free }}</ref><ref>{{cite journal |pmid=7550338 |year=1995 |last1=Patil |first1=N |title=A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation |journal=Nature Genetics |volume=11 |issue=2 |pages=126–129 |last2=Cox |first2=D. R |last3=Bhat |first3=D |last4=Faham |first4=M |last5=Myers |first5=R. M |last6=Peterson |first6=A. S |doi=10.1038/ng1095-126 |s2cid=23470275 }}</ref>
|-
|KCNH2 K<sup>+</sup> channel
|Cardiac, craniofacial patterning defects
|''Mus musculus''
|<ref>{{cite journal |pmid=18948620 |pmc=2774899 |year=2008 |last1=Teng |first1=G. Q. |title=Homozygous missense N629D hERG (KCNH2) potassium channel mutation causes developmental defects in the right ventricle and its outflow tract and embryonic lethality |journal=Circulation Research |volume=103 |issue=12 |pages=1483–1491 |last2=Zhao |first2=X. |last3=Lees-Miller |first3=J. P. |last4=Quinn |first4=F. R. |last5=Li |first5=P. |last6=Rancourt |first6=D. E. |last7=London |first7=B. |last8=Cross |first8=J. C. |last9=Duff |first9=H. J. |doi=10.1161/CIRCRESAHA.108.177055 }}</ref>
|-
|KCNQ1 K<sup>+</sup> channel
|Abnormalities of rectum, pancreas, and stomach
|''Mus musculus''
|<ref name="ReferenceC">{{cite journal |pmid=23975432 |pmc=3935979 |year=2014 |last1=Than |first1=B. L |title=The role of KCNQ1 in mouse and human gastrointestinal cancers |journal=Oncogene |volume=33 |issue=29 |pages=3861–3868 |last2=Goos |first2=J. A. |last3=Sarver |first3=A. L. |last4=O'Sullivan |first4=M. G. |last5=Rod |first5=A |last6=Starr |first6=T. K |last7=Fijneman |first7=R. J. |last8=Meijer |first8=G. A |last9=Zhao |first9=L |last10=Zhang |first10=Y |last11=Largaespada |first11=D. A. |last12=Scott |first12=P. M. |last13=Cormier |first13=R. T. |display-authors=3 |doi=10.1038/onc.2013.350 }}</ref>
|-
|NaV1.2
|Muscle and nerve repair defects
|''Xenopus''
|<ref name=pmid20881138/>
|-
|Kir6.1 K<sup>+</sup> channel
|Eye patterning defects
|''Xenopus''
|<ref name=pmid22159581/>
|-
|V-ATPase ion pump
|Left-right asymmetry defects, muscle and nerve repair
|''Xenopus, Gallus gallus domesticus, Danio rerio''
|<ref name=pmid17329365/><ref name=pmid16554361/>
|-
|H,K-ATPase ion pump
|Left-right asymmetry defects
|''Xenopus, Echinoidea''
|<ref>{{cite journal |pmid=24671205 |pmc=3966808 |year=2014 |last1=Monteiro |first1=J |title=V-ATPase proton pumping activity is required for adult zebrafish appendage regeneration |journal=PLOS ONE |volume=9 |issue=3 |pages=e92594 |last2=Aires |first2=R |last3=Becker |first3=J. D |last4=Jacinto |first4=A |last5=Certal |first5=A. C |last6=Rodríguez-León |first6=J |doi=10.1371/journal.pone.0092594 |bibcode=2014PLoSO...992594M |doi-access=free }}</ref><ref>{{cite journal |pmid=12372302 |year=2002 |last1=Levin |first1=M |title=Asymmetries in H+/K+-ATPase and cell membrane potentials comprise a very early step in left-right patterning |journal=Cell |volume=111 |issue=1 |pages=77–89 |last2=Thorlin |first2=T |last3=Robinson |first3=K. R |last4=Nogi |first4=T |last5=Mercola |first5=M |doi=10.1016/s0092-8674(02)00939-x|s2cid=2502945 |doi-access=free }}</ref><ref>{{cite journal |pmid=15992548 |year=2005 |last1=Duboc |first1=V |title=Left-right asymmetry in the sea urchin embryo is regulated by nodal signaling on the right side |journal=Developmental Cell |volume=9 |issue=1 |pages=147–158 |last2=Röttinger |first2=E |last3=Lapraz |first3=F |last4=Besnardeau |first4=L |last5=Lepage |first5=T |display-authors=3 |doi=10.1016/j.devcel.2005.05.008 |doi-access=free }}</ref>
|-
|Kir7.1 K<sup>+</sup> channel
|Melanosome development defects
|''Danio rerio''
|<ref>{{cite journal |pmid=17121467 |pmc=1657052 |year=2006 |last1=Iwashita |first1=M |title=Pigment pattern in jaguar/obelix zebrafish is caused by a Kir7.1 mutation: Implications for the regulation of melanosome movement |journal=PLOS Genetics |volume=2 |issue=11 |pages=e197 |last2=Watanabe |first2=M |last3=Ishii |first3=M |last4=Chen |first4=T |last5=Johnson |first5=S. L. |last6=Kurachi |first6=Y. |last7=Okada |first7=N. |last8=Kondo |first8=S. |display-authors=3 |doi=10.1371/journal.pgen.0020197 |doi-access=free }}</ref>
|-
|Kv channels
|Fin size regulation, heart size regulation
|''Danio rerio, Mus musculus''
|<ref name=pmid24453984/><ref>{{cite journal |pmid=27038296 |pmc=4827621 |year=2016 |last1=Tur |first1=J |title=Deletion of Kvβ1.1 subunit leads to electrical and haemodynamic changes causing cardiac hypertrophy in female murine hearts |journal=Experimental Physiology |volume=101 |issue=4 |pages=494–508 |last2=Chapalamadugu |first2=K. C |last3=Padawer |first3=T |last4=Badole |first4=S. L |last5=Kilfoil Pj |first5=2nd |last6=Bhatnagar |first6=A |last7=Tipparaju |first7=S. M |doi=10.1113/EP085405 }}</ref>
|-
|NaV 1.5, Na<sup>+</sup>/K<sup>+</sup>-ATPase
|Cardiac morphogenesis
|''Danio rerio''
|<ref>{{cite journal |pmid=20339120 |pmc=2869449 |year=2010 |last1=Chopra |first1=S. S |title=Voltage-gated sodium channels are required for heart development in zebrafish |journal=Circulation Research |volume=106 |issue=8 |pages=1342–1350 |last2=Stroud |first2=D. M |last3=Watanabe |first3=H |last4=Bennett |first4=J. S |last5=Burns |first5=C. G |last6=Wells |first6=K. S |last7=Yang |first7=T |last8=Zhong |first8=T. P |last9=Roden |first9=D. M |doi=10.1161/CIRCRESAHA.109.213132 }}</ref><ref>{{cite journal |pmid=14602677 |year=2003 |last1=Shu |first1=X |title=Na,K-ATPase is essential for embryonic heart development in the zebrafish |journal=Development |volume=130 |issue=25 |pages=6165–6173 |last2=Cheng |first2=K |last3=Patel |first3=N |last4=Chen |first4=F |last5=Joseph |first5=E |last6=Tsai |first6=H. J |last7=Chen |first7=J. N. |display-authors=3 |doi=10.1242/dev.00844 |doi-access=free }}</ref>
|-
|KCNC3
|Dominant mutations cause cerebellar displasia in humans, and wing venation and eye defects in Drosophila.
|''Homo sapiens, Drosophila''
|<ref>{{cite journal |pmid=28467418 |pmc=5414954 |year=2017 |last1=Khare |first1=S |title=A KCNC3 mutation causes a neurodevelopmental, non-progressive SCA13 subtype associated with dominant negative effects and aberrant EGFR trafficking |journal=PLOS ONE |volume=12 |issue=5 |pages=e0173565 |last2=Nick |first2=J. A |last3=Zhang |first3=Y |last4=Galeano |first4=K |last5=Butler |first5=B |last6=Khoshbouei |first6=H |last7=Rayaprolu |first7=S |last8=Hathorn |first8=T |last9=Ranum |first9=L. P. W |last10=Smithson |first10=L |last11=Golde |first11=T. E |last12=Paucar |first12=M |last13=Morse |first13=R |last14=Raff |first14=M |last15=Simon |first15=J |last16=Nordenskjöld |first16=M |last17=Wirdefeldt |first17=K |last18=Rincon-Limas |first18=D. E |last19=Lewis |first19=J |last20=Kaczmarek |first20=L. K |last21=Fernandez-Funez |first21=P |last22=Nick |first22=H. S |last23=Waters |first23=M. F. |display-authors=3 |doi=10.1371/journal.pone.0173565 |bibcode=2017PLoSO..1273565K |doi-access=free }}</ref>
|}

'''Table 2:''' Gap Junctions Implicated in Patterning

{| class="wikitable"
|-
!Gap Junction Protein
!Morphogenetic role or LOF phenotype
!Species
!References
|-
|Innexins
|Gonad and germline morphogenesis
|''C. Elegans''
|<ref>{{cite journal |pmid=25195067 |pmc=4224157 |year=2014 |last1=Starich |first1=T. A. |title=Two classes of gap junction channels mediate soma-germline interactions essential for germline proliferation and gametogenesis in Caenorhabditis elegans |journal=Genetics |volume=198 |issue=3 |pages=1127–1153 |last2=Hall |first2=D. H. |last3=Greenstein |first3=D. |doi=10.1534/genetics.114.168815 }}</ref>
|-
|Innexin1,2
|Cuticle (epithelial) patterning, foregut development
|''Drosophila''
|<ref>{{cite journal |pmid=15047872 |pmc=420120 |year=2004 |last1=Bauer |first1=R |title=Gap junction channel protein innexin 2 is essential for epithelial morphogenesis in the Drosophila embryo |journal=Molecular Biology of the Cell |volume=15 |issue=6 |pages=2992–3004 |last2=Lehmann |first2=C |last3=Martini |first3=J |last4=Eckardt |first4=F |last5=Hoch |first5=M |doi=10.1091/mbc.E04-01-0056 }}</ref><ref>{{cite journal |pmid=11956317 |url=http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=11956317 |year=2002 |last1=Bauer |first1=R |title=The Drosophila gap junction channel gene innexin 2 controls foregut development in response to Wingless signalling |journal=Journal of Cell Science |volume=115 |issue=Pt 9 |pages=1859–1867 |last2=Lehmann |first2=C |last3=Fuss |first3=B |last4=Eckardt |first4=F |last5=Hoch |first5=M. |display-authors=3 |doi=10.1242/jcs.115.9.1859}}</ref>
|-
|Innexin 2
|Eye size
|''Drosophila''
|<ref>{{cite journal |pmid=26455410 |year=2015 |last1=Richard |first1=M. |title=Drosophila eye size is determined by Innexin 2-dependent Decapentaplegic signalling |journal=Developmental Biology |volume=408 |issue=1 |pages=26–40 |last2=Hoch |first2=M |doi=10.1016/j.ydbio.2015.10.011 |doi-access=free }}</ref>
|-
|Cx43
|Oculodentodigital dysplasia (ODDD), heart defects (outflow tract and conotruncal), left-right asymmetry randomization, Osteoblast differentiation problems, craniofacial defects, myogenesis
|''Homo sapiens, Mus musculus, Gallus gallus domesticus''
|<ref>{{cite journal |pmid=16378922 |year=2005 |last1=Debeer |first1=P |title=Novel GJA1 mutations in patients with oculo-dento-digital dysplasia (ODDD) |journal=European Journal of Medical Genetics |volume=48 |issue=4 |pages=377–387 |last2=Van Esch |first2=H |last3=Huysmans |first3=C |last4=Pijkels |first4=E |last5=De Smet |first5=L |last6=Van De Ven |first6=W |last7=Devriendt |first7=K |last8=Fryns |first8=J. P |doi=10.1016/j.ejmg.2005.05.003 }}</ref><ref>{{cite journal |pmid=14974090 |year=2004 |last1=Pizzuti |first1=A |title=A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype |journal=Human Mutation |volume=23 |issue=3 |page=286 |last2=Flex |first2=E |last3=Mingarelli |first3=R |last4=Salpietro |first4=C |last5=Zelante |first5=L |last6=Dallapiccola |first6=B |doi=10.1002/humu.9220 |s2cid=13345970 |doi-access=free }}</ref><ref>{{cite journal |pmid=9118799 |year=1997 |last1=Ewart |first1=J. L |title=Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene |journal=Development |volume=124 |issue=7 |pages=1281–1292 |last2=Cohen |first2=M. F |last3=Meyer |first3=R. A |last4=Huang |first4=G. Y |last5=Wessels |first5=A |last6=Gourdie |first6=R. G |last7=Chin |first7=A. J |last8=Park |first8=S. M |last9=Lazatin |first9=B. O |last10=Villabon |first10=S |last11=Lo |first11=C. W |doi=10.1242/dev.124.7.1281 |s2cid=189036 }}</ref><ref>{{cite journal |pmid=7892609 |year=1995 |last1=Reaume |first1=A. G |title=Cardiac malformation in neonatal mice lacking connexin43 |journal=Science |volume=267 |issue=5205 |pages=1831–1834 |last2=De Sousa |first2=P. A |last3=Kulkarni |first3=S |last4=Langille |first4=B. L |last5=Zhu |first5=D |last6=Davies |first6=T. C |last7=Juneja |first7=S. C |last8=Kidder |first8=G. M |last9=Rossant |first9=J |doi=10.1126/science.7892609|bibcode=1995Sci...267.1831R }}</ref><ref>{{cite journal |pmid=7715640 |year=1995 |last1=Britz-Cunningham |first1=S. H |title=Mutations of the Connexin43 gap-junction gene in patients with heart malformations and defects of laterality |journal=New England Journal of Medicine |volume=332 |issue=20 |pages=1323–1329 |last2=Shah |first2=M. M |last3=Zuppan |first3=C. W |last4=Fletcher |first4=W. H |doi=10.1056/NEJM199505183322002 |doi-access=free }}</ref><ref>{{cite journal |pmid=18424255 |pmc=2441851 |year=2008 |last1=Civitelli |first1=R |title=Cell-cell communication in the osteoblast/osteocyte lineage |journal=Archives of Biochemistry and Biophysics |volume=473 |issue=2 |pages=188–192 |doi=10.1016/j.abb.2008.04.005 }}</ref><ref>{{cite journal |pmid=10518488 |year=1999 |last1=Levin |first1=M |title=Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node |journal=Development |volume=126 |issue=21 |pages=4703–4714 |last2=Mercola |first2=M |doi=10.1242/dev.126.21.4703 }}</ref><ref>{{cite journal |pmid=10079509 |year=1999 |last1=Becker |first1=D. L |title=Roles for alpha 1 connexin in morphogenesis of chick embryos revealed using a novel antisense approach |journal=Developmental Genetics |volume=24 |issue=1–2 |pages=33–42 |last2=McGonnell |first2=I |last3=Makarenkova |first3=H. P |last4=Patel |first4=K |last5=Tickle |first5=C |last6=Lorimer |first6=J |last7=Green |first7=C. R |doi=10.1002/(SICI)1520-6408(1999)24:1/2<33::AID-DVG5>3.0.CO;2-F }}</ref><ref>{{cite journal |pmid=11076975 |pmc=2169447 |year=2000 |last1=Lecanda |first1=F |title=Connexin43 deficiency causes delayed ossification, craniofacial abnormalities, and osteoblast dysfunction |journal=The Journal of Cell Biology |volume=151 |issue=4 |pages=931–944 |last2=Warlow |first2=P. M |last3=Sheikh |first3=S |last4=Furlan |first4=F |last5=Steinberg |first5=T. H |last6=Civitelli |first6=R |doi=10.1083/jcb.151.4.931}}</ref><ref>{{cite journal |pmid=14681056 |year=2003 |last1=Araya |first1=R |title=Presence and importance of connexin43 during myogenesis |journal=Cell Communication & Adhesion |volume=10 |issue=4–6 |pages=451–456 |last2=Eckardt |first2=D |last3=Riquelme |first3=M. A |last4=Willecke |first4=K |last5=Sáez |first5=J. C |doi=10.1080/cac.10.4-6.451.456|s2cid=33491307 |hdl=10533/174413 |hdl-access=free }}</ref>{{excessive citations inline|date=November 2023}}
|-
|Cx37
|Lymphatic system patterning
|''Mus musculus''
|<ref>{{cite journal |pmid=21515254 |pmc=3134316 |year=2011 |last1=Kanady |first1=J. D |title=Connexin37 and Connexin43 deficiencies in mice disrupt lymphatic valve development and result in lymphatic disorders including lymphedema and chylothorax |journal=Developmental Biology |volume=354 |issue=2 |pages=253–266 |last2=Dellinger |first2=M. T |last3=Munger |first3=S. J |last4=Witte |first4=M. H |last5=Simon |first5=A. M |doi=10.1016/j.ydbio.2011.04.004 }}</ref><ref>{{cite journal |pmid=26079578 |pmc=4529811 |year=2015 |last1=Kanady |first1=J. D |title=Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling |journal=Developmental Biology |volume=405 |issue=1 |pages=33–46 |last2=Munger |first2=S. J |last3=Witte |first3=M. H |last4=Simon |first4=A. M |doi=10.1016/j.ydbio.2015.06.004 }}</ref>
|-
|Cx45
|Cardiac defects (cushion patterning)
|''Mus musculus''
|<ref>{{cite journal |pmid=10903175 |year=2000 |last1=Kumai |first1=M |title=Loss of connexin45 causes a cushion defect in early cardiogenesis |journal=Development |volume=127 |issue=16 |pages=3501–3512 |last2=Nishii |first2=K |last3=Nakamura |first3=K |last4=Takeda |first4=N |last5=Suzuki |first5=M |last6=Shibata |first6=Y |doi=10.1242/dev.127.16.3501 }}</ref><ref>{{cite journal |pmid=11673050 |year=2001 |last1=Nishii |first1=K |title=Regulation of the epithelial-mesenchymal transformation through gap junction channels in heart development |journal=Trends in Cardiovascular Medicine |volume=11 |issue=6 |pages=213–218 |last2=Kumai |first2=M |last3=Shibata |first3=Y |doi=10.1016/s1050-1738(01)00103-7}}</ref>
|-
|Cx50, Cx46
|Eye defects (differentiation and proliferation problems, especially lens),
|''Mus musculus''
|<ref>{{cite journal |pmid=11786642 |year=2002 |last1=White |first1=T. W |title=Unique and redundant connexin contributions to lens development |journal=Science |volume=295 |issue=5553 |pages=319–320 |doi=10.1126/science.1067582 |bibcode=2002Sci...295..319W |s2cid=25744002 }}</ref>
|-
|Cx26
|Cochlear development defects
|''Mus musculus''
|<ref>{{cite journal |pmid=25251605 |year=2015 |last1=Chang |first1=Q |title=Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing |journal=Neurobiology of Disease |volume=73 |pages=418–427 |last2=Tang |first2=W |last3=Kim |first3=Y |last4=Lin |first4=X |doi=10.1016/j.nbd.2014.09.005 |s2cid=207068577 }}</ref>
|-
|Cx41.8
|Pigmentation pattern defects
|''Danio rerio''
|<ref>{{cite journal |pmid=16845369 |pmc=1559663 |year=2006 |last1=Watanabe |first1=M |title=Spot pattern of leopard Danio is caused by mutation in the zebrafish connexin41.8 gene |journal=EMBO Reports |volume=7 |issue=9 |pages=893–897 |last2=Iwashita |first2=M |last3=Ishii |first3=M |last4=Kurachi |first4=Y |last5=Kawakami |first5=A |last6=Kondo |first6=S |last7=Okada |first7=N |doi=10.1038/sj.embor.7400757 }}</ref>
|-
|Cx43
|Fin size and pattern regulation<br />Craniofrontonasal syndrome
|''Danio rerio, Mus musculus''
|<ref>{{cite journal |pmid=15649473 |year=2005 |last1=Iovine |first1=M. K |title=Mutations in connexin43 (GJA1) perturb bone growth in zebrafish fins |journal=Developmental Biology |volume=278 |issue=1 |pages=208–219 |last2=Higgins |first2=E. P |last3=Hindes |first3=A |last4=Coblitz |first4=B |last5=Johnson |first5=S. L |doi=10.1016/j.ydbio.2004.11.005 |doi-access=free }}</ref><ref>{{cite journal |pmid=16968134 |pmc=1563491 |year=2006 |last1=Davy |first1=A |title=Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome |journal=PLOS Biology |volume=4 |issue=10 |pages=e315 |last2=Bush |first2=J. O |last3=Soriano |first3=P |doi=10.1371/journal.pbio.0040315 |doi-access=free }}</ref><ref>{{cite journal |pmid=19150347 |pmc=2913275 |year=2009 |last1=Sims Jr |first1=K |title=Connexin43 regulates joint location in zebrafish fins |journal=Developmental Biology |volume=327 |issue=2 |pages=410–418 |last2=Eble |first2=D. M |last3=Iovine |first3=M. K |doi=10.1016/j.ydbio.2008.12.027 }}</ref><ref>{{cite journal |pmid=18406403 |pmc=2429987 |year=2008 |last1=Hoptak-Solga |first1=A. D |title=Connexin43 (GJA1) is required in the population of dividing cells during fin regeneration |journal=Developmental Biology |volume=317 |issue=2 |pages=541–548 |last2=Nielsen |first2=S |last3=Jain |first3=I |last4=Thummel |first4=R |last5=Hyde |first5=D. R |last6=Iovine |first6=M. K |doi=10.1016/j.ydbio.2008.02.051 }}</ref>
|-
|Inx4,Inx2
|Germline differentiation and spermatogenesis
|''Drosophila''
|<ref>{{cite journal |pmid=26116660 |year=2015 |last1=Smendziuk |first1=C. M |title=Bi-directional gap junction-mediated soma-germline communication is essential for spermatogenesis |journal=Development |volume=142 |issue=15 |pages=2598–2609 |last2=Messenberg |first2=A |last3=Vogl |first3=A. W |last4=Tanentzapf |first4=G |doi=10.1242/dev.123448 |pmc=6514411}}</ref>
|-
|Pannexin3
|Skeletal development
|''Mus musculus''
|<ref>{{cite journal |pmid=26183770 |year=2015 |last1=Oh |first1=S. K |title=Pannexin 3 is required for normal progression of skeletal development in vertebrates |journal=The FASEB Journal |volume=29 |issue=11 |pages=4473–4484 |last2=Shin |first2=J. O |last3=Baek |first3=J. I |last4=Lee |first4=J |last5=Bae |first5=J. W |last6=Ankamerddy |first6=H |last7=Kim |first7=M. J |last8=Huh |first8=T. L |last9=Ryoo |first9=Z. Y |last10=Kim |first10=U. K |last11=Bok |first11=J |last12=Lee |first12=K. Y |doi=10.1096/fj.15-273722 |doi-access=free |s2cid=8219978 }}</ref>
|}

'''Table 3:''' Ion Channel Oncogenes

{| class="wikitable"
|-
!Protein
!Species
!References
!Cancer-role
|-
|NaV 1.5 channel
|''Homo sapiens''
|<ref>{{cite journal |pmid=19835862 |year=2009 |last1=Onkal |first1=R |title=Molecular pharmacology of voltage-gated sodium channel expression in metastatic disease: Clinical potential of neonatal Nav1.5 in breast cancer |journal=European Journal of Pharmacology |volume=625 |issue=1–3 |pages=206–219 |last2=Djamgoz |first2=M. B |doi=10.1016/j.ejphar.2009.08.040 }}</ref><ref name="ReferenceD">{{cite journal |pmid=20651255 |pmc=2936697 |year=2010 |last1=House |first1=C. D |title=Voltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion |journal=Cancer Research |volume=70 |issue=17 |pages=6957–6967 |last2=Vaske |first2=C. J |last3=Schwartz |first3=A. M |last4=Obias |first4=V |last5=Frank |first5=B |last6=Luu |first6=T |last7=Sarvazyan |first7=N |last8=Irby |first8=R |last9=Strausberg |first9=R. L |last10=Hales |first10=T. G |last11=Stuart |first11=J. M |last12=Lee |first12=N. H |doi=10.1158/0008-5472.CAN-10-1169 }}</ref>
|Oncogene
|-
|ERG potassium channels
|''Homo sapiens''
|<ref>{{cite journal |pmid=25945833 |pmc=5312283 |year=2016 |last1=Perez-Neut |first1=M |title=HERG1/Kv11.1 activation stimulates transcription of p21waf/cip in breast cancer cells via a calcineurin-dependent mechanism |journal=Oncotarget |volume=7 |issue=37 |pages=58893–58902 |last2=Rao |first2=V. R |last3=Gentile |first3=S |doi=10.18632/oncotarget.3797}}</ref><ref>{{cite journal |pmid=23744352 |pmc=3698542 |year=2013 |last1=Lansu |first1=K |title=Potassium channel activation inhibits proliferation of breast cancer cells by activating a senescence program |journal=Cell Death & Disease |volume=4 |issue=6 |pages=e652 |last2=Gentile |first2=S |doi=10.1038/cddis.2013.174 }}</ref>
|Oncogene
|-
|9 potassium channel
|''Mus musculus''
|<ref>{{cite journal |pmid=12782791 |pmc=164668 |year=2003 |last1=Pei |first1=L |title=Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function |journal=Proceedings of the National Academy of Sciences |volume=100 |issue=13 |pages=7803–7807 |last2=Wiser |first2=O |last3=Slavin |first3=A |last4=Mu |first4=D |last5=Powers |first5=S |last6=Jan |first6=L. Y |last7=Hoey |first7=T |doi=10.1073/pnas.1232448100 |bibcode=2003PNAS..100.7803P |doi-access=free }}</ref>
|Oncogene
|-
|Ductin (proton V-ATPase component)
|''Mus musculus''
|<ref>{{cite journal |doi=10.1038/sj.onc.1202092 |pmid=9796696 |title=Induction of cell transformation by mutated 16K vacuolar H+-atpase (ductin) is accompanied by down-regulation of gap junctional intercellular communication and translocation of connexin 43 in NIH3T3 cells |journal=Oncogene |volume=17 |issue=13 |pages=1673–1680 |year=1998 |last1=Saito |first1=Tsuyoshi |last2=Schlegel |first2=Richard |last3=Andresson |first3=Thirkell |last4=Yuge |first4=Louis |last5=Yamamoto |first5=Masao |last6=Yamasaki |first6=Hiroshi |doi-access=free }}</ref>
|Oncogene
|-
|SLC5A8 sodium/butyrate transporter
|''Homo sapiens''
|<ref>{{cite journal |pmid=16375929 |year=2006 |last1=Gupta |first1=N |title=SLC5A8 (SMCT1)-mediated transport of butyrate forms the basis for the tumor suppressive function of the transporter |journal=Life Sciences |volume=78 |issue=21 |pages=2419–2425 |last2=Martin |first2=P. M |last3=Prasad |first3=P. D |last4=Ganapathy |first4=V |doi=10.1016/j.lfs.2005.10.028 }}</ref>
|Oncogene
|-
|KCNE2 potassium channel
|''Mus musculus''
|<ref>{{cite journal |pmid=20625512 |pmc=2897890 |year=2010 |last1=Roepke |first1=T. K |title=Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia |journal=PLOS ONE |volume=5 |issue=7 |pages=e11451 |last2=Purtell |first2=K |last3=King |first3=E. C |last4=La Perle |first4=K. M |last5=Lerner |first5=D. J |last6=Abbott |first6=G. W |doi=10.1371/journal.pone.0011451 |bibcode=2010PLoSO...511451R |doi-access=free }}</ref>
|Oncogene
|-
|KCNQ1 potassium channel
|''Homo sapiens'', mouse
|<ref name=pmid11751681/><ref name="ReferenceC"/><ref>{{cite journal |pmid=9020845 |year=1997 |last1=Lee |first1=M. P |title=Human KVLQT1 gene shows tissue-specific imprinting and encompasses Beckwith-Wiedemann syndrome chromosomal rearrangements |journal=Nature Genetics |volume=15 |issue=2 |pages=181–185 |last2=Hu |first2=R. J |last3=Johnson |first3=L. A |last4=Feinberg |first4=A. P. |display-authors=3 |doi=10.1038/ng0297-181 |s2cid=24715509 }}</ref>
|Oncogene
|-
|SCN5A voltage-gated sodium channel
|''Homo sapiens''
|<ref name="ReferenceD"/>
|Oncogene
|-
|Metabotropic glutamate receptor
|''Mus musculus'', Human
|<ref>{{cite journal |pmid=23085756 |pmc=3910169 |year=2013 |last1=Martino |first1=J. J |title=Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells |journal=Oncogene |volume=32 |issue=37 |pages=4366–4376 |last2=Wall |first2=B. A |last3=Mastrantoni |first3=E |last4=Wilimczyk |first4=B. J |last5=La Cava |first5=S. N |last6=Degenhardt |first6=K |last7=White |first7=E |last8=Chen |first8=S |doi=10.1038/onc.2012.471 }}</ref><ref>{{cite journal |pmid=21681448 |pmc=3898178 |year=2012 |last1=Speyer |first1=C. L |title=Metabotropic glutamate receptor-1: A potential therapeutic target for the treatment of breast cancer |journal=Breast Cancer Research and Treatment |volume=132 |issue=2 |pages=565–573 |last2=Smith |first2=J. S |last3=Banda |first3=M |last4=Devries |first4=J. A |last5=Mekani |first5=T |last6=Gorski |first6=D. H. |display-authors=3 |doi=10.1007/s10549-011-1624-x }}</ref>
|Oncogene
|-
|CFTR chloride channel
|''Homo sapiens''
|<ref>{{cite journal |pmid=23916755 |year=2013 |last1=Zhang |first1=J. T |title=Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |volume=1833 |issue=12 |pages=2961–2969 |last2=Jiang |first2=X. H |last3=Xie |first3=C |last4=Cheng |first4=H |last5=Da Dong |first5=J |last6=Wang |first6=Y |last7=Fok |first7=K. L |last8=Zhang |first8=X. H |last9=Sun |first9=T. T |last10=Tsang |first10=L. L |last11=Chen |first11=H |last12=Sun |first12=X. J |last13=Chung |first13=Y. W |last14=Cai |first14=Z. M |last15=Jiang |first15=W. G |last16=Chan |first16=H. C |doi=10.1016/j.bbamcr.2013.07.021 |doi-access=free }}</ref><ref>{{cite journal |pmid=22797075 |year=2013 |last1=Xie |first1=C |title=CFTR suppresses tumor progression through miR-193b targeting urokinase plasminogen activator (uPA) in prostate cancer |journal=Oncogene |volume=32 |issue=18 |pages=2282–2291, 2291.e1–7 |last2=Jiang |first2=X. H |last3=Zhang |first3=J. T |last4=Sun |first4=T. T |last5=Dong |first5=J. D |last6=Sanders |first6=A. J |last7=Diao |first7=R. Y |last8=Wang |first8=Y |last9=Fok |first9=K. L |last10=Tsang |first10=L. L |last11=Yu |first11=M. K |last12=Zhang |first12=X. H |last13=Chung |first13=Y. W |last14=Ye |first14=L |last15=Zhao |first15=M. Y |last16=Guo |first16=J. H |last17=Xiao |first17=Z. J |last18=Lan |first18=H. Y |last19=Ng |first19=C. F |last20=Lau |first20=K. M |last21=Cai |first21=Z. M |last22=Jiang |first22=W. G |last23=Chan |first23=H. C. |display-authors=3 |doi=10.1038/onc.2012.251 |s2cid=21255355 }}</ref>
|Tumor suppressor
|-
|Connexin43
|''Homo sapiens''
|<ref>{{cite journal |pmid=21866551 |year=2012 |last1=Sirnes |first1=S. |title=Connexin43 acts as a colorectal cancer tumor suppressor and predicts disease outcome |journal=International Journal of Cancer |volume=131 |issue=3 |pages=570–581 |last2=Bruun |first2=J. |last3=Kolberg |first3=M. |last4=Kjenseth |first4=A. |last5=Lind |first5=G. E. |last6=Svindland |first6=A. |last7=Brech |first7=A. |last8=Nesbakken |first8=A. |last9=Lothe |first9=R. A. |last10=Leithe |first10=E. |last11=Rivedal |first11=E. |display-authors=3 |doi=10.1002/ijc.26392 |s2cid=6293505 }}</ref>
|Tumor suppressor
|-
|BKCa
|''Homo sapiens''
|<ref>{{cite journal |pmid=25422049 |pmc=4306270 |year=2015 |last1=Schickling |first1=B. M |title=BKCa channel inhibitor modulates the tumorigenic ability of hormone-independent breast cancer cells via the Wnt pathway |journal=Oncology Reports |volume=33 |issue=2 |pages=533–538 |last2=England |first2=S. K |last3=Aykin-Burns |first3=N |last4=Norian |first4=L. A |last5=Leslie |first5=K. K |last6=Frieden-Korovkina |first6=V. P. |display-authors=3 |doi=10.3892/or.2014.3617 }}</ref>
|Oncogene
|-
|Muscarinic Acetylcholine receptor
|''Homo sapiens, Mus musculus''
|<ref>{{cite journal |pmid=7680475 |pmc=45948 |year=1993 |last1=Felder |first1=C. C. |title=Tumor-suppressor function of muscarinic acetylcholine receptors is associated with activation of receptor-operated calcium influx |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=90 |issue=5 |pages=1706–1710 |last2=MacArthur |first2=L |last3=Ma |first3=A. L |last4=Gusovsky |first4=F |last5=Kohn |first5=E. C. |display-authors=3 |doi=10.1073/pnas.90.5.1706|bibcode=1993PNAS...90.1706F |doi-access=free }}</ref>
|Tumor suppressor
|-
|KCNJ3 (Girk)
|''Homo sapiens''
|<ref>{{cite journal |pmid=27519272 |pmc=4983040 |year=2016 |last1=Rezania |first1=S |title=Overexpression of KCNJ3 gene splice variants affects vital parameters of the malignant breast cancer cell line MCF-7 in an opposing manner |journal=BMC Cancer |volume=16 |page=628 |last2=Kammerer |first2=S |last3=Li |first3=C |last4=Steinecker-Frohnwieser |first4=B |last5=Gorischek |first5=A |last6=Devaney |first6=T. T |last7=Verheyen |first7=S |last8=Passegger |first8=C. A |last9=Tabrizi-Wizsy |first9=N. G |last10=Hackl |first10=H |last11=Platzer |first11=D |last12=Zarnani |first12=A. H |last13=Malle |first13=E |last14=Jahn |first14=S. W |last15=Bauernhofer |first15=T |last16=Schreibmayer |first16=W |doi=10.1186/s12885-016-2664-8 |doi-access=free }}</ref><ref>{{cite journal |pmid=27835900 |pmc=5356693 |year=2016 |last1=Kammerer |first1=S |title=KCNJ3 is a new independent prognostic marker for estrogen receptor positive breast cancer patients |journal=Oncotarget |volume=7 |issue=51 |pages=84705–84717 |last2=Sokolowski |first2=A |last3=Hackl |first3=H |last4=Platzer |first4=D |last5=Jahn |first5=S. W |last6=El-Heliebi |first6=A |last7=Schwarzenbacher |first7=D |last8=Stiegelbauer |first8=V |last9=Pichler |first9=M |last10=Rezania |first10=S |last11=Fiegl |first11=H |last12=Peintinger |first12=F |last13=Regitnig |first13=P |last14=Hoefler |first14=G |last15=Schreibmayer |first15=W |last16=Bauernhofer |first16=T. |display-authors=3 |doi=10.18632/oncotarget.13224}}</ref>
|Oncogene
|}

==References==
{{reflist}}

==External links==
* {{wikiquote-inline}}

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