View source for Gap junction

{{Short description|Cell-cell junction composed of innexins or connexins}}
{{Tone|date=April 2024}}
{{Infobox anatomy
| Name        = Gap junction
| Latin       =
| Image       = Gap_cell_junction-en.svg
| Caption     = Vertebrate gap junction
| Image2      =
| Caption2    =
| Precursor   =
| System      =
| Artery      =
| Vein        =
| Nerve       =
| Lymph       =
}}
'''Gap junctions''' are [[Membrane channel|membrane channels]] between adjacent cells that allow the direct exchange of cytoplasmic substances, such as small molecules, substrates, and metabolites.<ref name="Talukdar">{{cite journal |last1=Talukdar |first1=S |last2=Emdad |first2=L |last3=Das |first3=SK |last4=Fisher |first4=PB |title=GAP junctions: multifaceted regulators of neuronal differentiation. |journal=Tissue Barriers |date=2 January 2022 |volume=10 |issue=1 |article-number=1982349 |doi=10.1080/21688370.2021.1982349 |pmid=34651545|pmc=8794256 }}</ref>

Gap junctions were first described as ''close appositions'' alongside tight junctions, however, electron microscopy studies in 1967 led to gap junctions being named as such to be distinguished from tight junctions.<ref>{{cite journal |vauthors=Brightman MW, Reese TS |title=Junctions between intimately apposed cell membranes in the vertebrate brain |date=March 1969 |journal=J. Cell Biol. |volume=40 |issue=3 |pages=648–677 |pmid=5765759 |pmc=2107650 |doi=10.1083/jcb.40.3.648}}</ref> They bridge a 2-4 nm gap between cell membranes.<ref>{{cite journal |last1=Revel |first1=J. P. |last2=Karnovsky |first2=M. J. |title=Hexagonal Array of Subunits in Intercellular Junctions of the Mouse Heart and Liver |journal=Journal of Cell Biology |date=1 June 1967 |volume=33 |issue=3 |pages=C7–12 |doi=10.1083/jcb.33.3.C7|pmid=6036535 |pmc=2107199 }}</ref>

Gap junctions use protein complexes known as [[connexon]]s, composed of [[connexin]] proteins to connect one cell to another. [[Gap junction protein]]s include the more than 26 types of connexin, as well as at least 12 non-connexin components that make up the gap junction complex or ''nexus,''<ref>{{cite journal |last1=Hervé |first1=Jean-Claude |last2=Bourmeyster |first2=Nicolas |last3=Sarrouilhe |first3=Denis |last4=Duffy |first4=Heather S. |title=Gap junctional complexes: From partners to functions |journal=Progress in Biophysics and Molecular Biology |date=May 2007 |volume=94 |issue=1–2 |pages=29–65 |doi=10.1016/j.pbiomolbio.2007.03.010|pmid=17507078 }}</ref> including the [[tight junction protein ZO-1]]—a protein that holds membrane content together and adds structural clarity to a cell,<ref name="Connexin 43 gap junction plaque end">{{cite journal |last1=Gilleron |first1=Jérome |last2=Carette |first2=Diane |last3=Fiorini |first3=Céline |last4=Benkdane |first4=Merieme |last5=Segretain |first5=Dominique |last6=Pointis |first6=Georges |title=Connexin 43 gap junction plaque endocytosis implies molecular remodelling of ZO-1 and c-Src partners |journal=Communicative & Integrative Biology |date=March 2009 |volume=2 |issue=2 |pages=104–106 |doi=10.4161/cib.7626|pmid=19704902 |pmc=2686357 }}</ref> [[sodium channel]]s,<ref name="Localization of Na + channel cluste" /> and [[aquaporin]].<ref>{{cite journal |last1=Yu |first1=Xun Sean |last2=Yin |first2=Xinye |last3=Lafer |first3=Eileen M. |last4=Jiang |first4=Jean X. |title=Developmental Regulation of the Direct Interaction between the Intracellular Loop of Connexin 45.6 and the C Terminus of Major Intrinsic Protein (Aquaporin-0) |journal=Journal of Biological Chemistry |date=June 2005 |volume=280 |issue=23 |pages=22081–22090 |doi=10.1074/jbc.M414377200|doi-access=free |pmid=15802270 }}</ref><ref name="Gruijters, WTM 1989 509–13" />

More gap junction proteins have become known due to the development of [[next-generation sequencing]]. Connexins were found to be structurally homologous between vertebrates and invertebrates but different in sequence.<ref>{{cite journal |last1=Phelan |first1=Pauline |last2=Stebbings |first2=Lucy A. |last3=Baines |first3=Richard A. |last4=Bacon |first4=Jonathan P. |last5=Davies |first5=Jane A. |last6=Ford |first6=Chris |title=Drosophila Shaking-B protein forms gap junctions in paired Xenopus oocytes |journal=Nature |date=January 1998 |volume=391 |issue=6663 |pages=181–184 |doi=10.1038/34426|pmid=9428764 |bibcode=1998Natur.391..181P |s2cid=205003383 }}</ref> As a result, the term [[innexin]] is used to differentiate invertebrate connexins.<ref>{{cite journal |last1=Phelan |first1=Pauline |last2=Bacon |first2=Jonathan P. |last3=A. Davies |first3=Jane |last4=Stebbings |first4=Lucy A. |last5=Todman |first5=Martin G. |title=Innexins: a family of invertebrate gap-junction proteins |journal=Trends in Genetics |date=September 1998 |volume=14 |issue=9 |pages=348–349 |doi=10.1016/s0168-9525(98)01547-9|pmid=9769729 |pmc=4442478 }}</ref> There are more than 20 known innexins,<ref>{{cite journal |last1=Ortiz |first1=Jennifer |last2=Bobkov |first2=Yuriy V |last3=DeBiasse |first3=Melissa B |last4=Mitchell |first4=Dorothy G |last5=Edgar |first5=Allison |last6=Martindale |first6=Mark Q |last7=Moss |first7=Anthony G |last8=Babonis |first8=Leslie S |last9=Ryan |first9=Joseph F |title=Independent Innexin Radiation Shaped Signaling in Ctenophores |journal=Molecular Biology and Evolution |date=3 February 2023 |volume=40 |issue=2 |article-number=msad025 |doi=10.1093/molbev/msad025|pmid=36740225 |pmc=9949713 }}</ref> along with unnexins in parasites and [[vinnexin]]s in viruses.

An [[electrical synapse]] is a gap junction that can transmit [[action potential]]s between [[neuron]]s. Such synapses create bidirectional continuous-time electrical coupling<ref name=":0" /><ref name=":1" /> between neurons. Connexon pairs act as generalized regulated gates for ions and smaller molecules between cells. Hemichannel connexons form channels to the extracellular environment.<ref>{{cite journal |last1=Furshpan |first1=E. J. |last2=Potter |first2=D. D. |title=Mechanism of Nerve-Impulse Transmission at a Crayfish Synapse |journal=Nature |date=August 1957 |volume=180 |issue=4581 |pages=342–343 |doi=10.1038/180342a0|pmid=13464833 |bibcode=1957Natur.180..342F |s2cid=4216387 }}</ref><ref name="gj1">{{Cite journal|pmid=15109565 |year=2004 |first1=Paul D. |last1=Lampe |first2=Alan F. |last2=Lau |title=The effects of connexin phosphorylation on gap junctional communication |volume=36 |issue=7 |pages=1171–86 |doi=10.1016/S1357-2725(03)00264-4 |journal=The International Journal of Biochemistry & Cell Biology |pmc=2878204}}</ref><ref name="gj2">{{Cite journal|pmid=11368307 |year=2000 |first1=Paul D. |last1=Lampe |first2=Alan F. |last2=Lau |title=Regulation of gap junctions by phosphorylation of connexins |volume=384 |issue=2 |pages=205–15 |doi=10.1006/abbi.2000.2131 |journal=Archives of Biochemistry and Biophysics}}</ref><ref>{{cite journal |last1=Scemes |first1=Eliana |last2=Spray |first2=David C. |last3=Meda |first3=Paolo |title=Connexins, pannexins, innexins: novel roles of "hemi-channels" |journal=Pflügers Archiv: European Journal of Physiology |date=April 2009 |volume=457 |issue=6 |pages=1207–1226 |doi=10.1007/s00424-008-0591-5|pmid=18853183 |pmc=2656403 }}</ref>

A gap junction or ''macula communicans'' is different from an [[ephaptic coupling]] that involves electrical signals external to the cells.<ref>{{cite journal |last1=Martinez-Banaclocha |first1=Marcos |title=Astroglial Isopotentiality and Calcium-Associated Biomagnetic Field Effects on Cortical Neuronal Coupling |journal=Cells |date=13 February 2020 |volume=9 |issue=2 |page=439 |doi=10.3390/cells9020439|doi-access=free |pmid=32069981 |pmc=7073214 }}</ref><ref>{{cite journal |last1=Parker |first1=David |title=Neurobiological reduction: From cellular explanations of behavior to interventions |journal=Frontiers in Psychology |date=22 December 2022 |volume=13 |article-number=987101 |doi=10.3389/fpsyg.2022.987101|doi-access=free |pmid=36619115 |pmc=9815460 }}</ref>

==Structure==
[[File:Camillo Peracchia fig4-6.png|thumb|left|Connexon pairing across membranes bridges the gap between two cells and between vesicles to membranes.<ref name="globules">{{cite journal |last1=Peracchia |first1=Camillo |title=Low Resistance Junctions in Crayfish |journal=Journal of Cell Biology |date=1 April 1973 |volume=57 |issue=1 |pages=66–76 |doi=10.1083/jcb.57.1.66|pmid=4120611 |pmc=2108946 }}</ref>]]In [[vertebrate]]s, gap junction [[hemichannel]]s are primarily homo- or hetero-[[hexamer]]s of [[connexin]] [[protein]]s. Hetero-hexamers at gap junction plaques, help form a uniform intercellular space of 2-4&nbsp;nm.<ref name="maeda">{{Cite journal|pmid=19340074 |year=2009 |first1=Shoji |last1=Maeda |first2=So |last2=Nakagawa |first3=Michihiro |last3=Suga |first4=Eiki |last4=Yamashita |first5=Atsunori |last5=Oshima |first6=Yoshinori |last6=Fujiyoshi |first7=Tomitake |last7=Tsukihara |title=Structure of the connexin 26 gap junction channel at 3.5 A resolution |volume=458 |issue=7238 |pages=597–602 |doi=10.1038/nature07869 |journal=Nature|bibcode = 2009Natur.458..597M |s2cid=4431769 }}</ref> In this way hemichannels in the membrane of each cell are aligned with one another forming an [[intercellular communication]] path.<ref>{{Cite journal|pmid=9514740 |year=1998 |first1=Guy A. |last1=Perkins |first2=Daniel A. |last2=Goodenough |first3=Gina E. |last3=Sosinsky |title=Formation of the gap junction intercellular channel requires a 30 degree rotation for interdigitating two apposing connexons |volume=277 |issue=2 |pages=171–7 |journal=Journal of Molecular Biology |doi=10.1006/jmbi.1997.1580}}</ref>

[[Invertebrate]] gap junctions comprise [[protein]]s from the [[innexin]] [[protein family|family]]. Innexins have no significant sequence [[Homology (biology)|homology]] with connexins.<ref>{{cite journal|author=The C. elegans Sequencing Consortium |title=Genome sequence of the nematode C. elegans: a platform for investigating biology|journal=Science |date=Dec 11, 1998|volume=282|issue=5396|pages=2012–2018|pmid=9851916|doi=10.1126/science.282.5396.2012 |bibcode=1998Sci...282.2012.}}</ref> Though differing in sequence to connexins, innexins are similar enough to connexins to form gap junctions ''in vivo'' in the same way connexins do.<ref>{{cite journal|last1=Ganfornina|first1=MD|last2=Sánchez|first2=D|last3=Herrera |first3=M|last4=Bastiani|first4=MJ|title=Developmental expression and molecular characterization of two gap junction channel proteins expressed during embryogenesis in the grasshopper Schistocerca americana |journal=Developmental Genetics|date=1999|volume=24|issue=1–2|pages=137–150|pmid=10079517 |doi=10.1002/(SICI)1520-6408(1999)24:1/2<137::AID-DVG13>3.0.CO;2-7|hdl=10261/122956}}</ref><ref>{{cite journal|last1=Starich|first1=T. A.|title=eat-5 and unc-7 represent a multigene family in Caenorhabditis elegans involved in cell-cell coupling|journal=J. Cell Biol.|date=1996|volume=134|issue=2|pages=537–548|pmc=2120886|doi=10.1083/jcb.134.2.537 |pmid=8707836}}</ref><ref>{{cite journal|last1=Simonsen |first1=Karina T.|last2=Moerman|first2=Donald G.|last3=Naus|first3=Christian C.|title=Gap junctions in C. elegans|journal=Frontiers in Physiology|volume=5|page=40 |doi=10.3389/fphys.2014.00040|pmid=24575048 |pmc=3920094|year=2014|doi-access=free}}</ref>

The more recently characterized [[pannexin]] family,<ref>{{cite journal|last1=Barbe|first1=M. T.|title=Cell-Cell Communication Beyond Connexins: The Pannexin Channels|journal=Physiology|date=1 April 2006|volume=21|issue=2|pages=103–114|pmid=16565476 |doi=10.1152/physiol.00048.2005}}</ref> which was originally thought to form intercellular channels (with an [[amino acid]] sequence similar to innexins<ref>{{cite journal|last1=Panchina|first1=Yuri |last2=Kelmanson|first2=Ilya|last3=Matz|first3=Mikhail|last4=Lukyanov|first4=Konstantin|last5=Usman |first5=Natalia|last6=Lukyanov |first6=Sergey|title=A ubiquitous family of putative gap junction molecules|journal=Current Biology|volume=10|issue=13|pages=R473–R474|doi=10.1016/S0960-9822(00)00576-5|pmid=10898987|date=June 2000|s2cid=20001454|doi-access=free|bibcode=2000CBio...10.R473P }}</ref>) in fact functions as a single-membrane channel that communicates with the extracellular environment and has been shown to pass calcium and [[Adenosine triphosphate|ATP]].<ref>{{cite journal|last1=Lohman |first1=Alexander W. |last2=Isakson|first2=Brant E.|title=Differentiating connexin hemichannels and pannexin channels in cellular ATP release|journal=FEBS Letters|volume=588|issue=8|pages=1379–1388|pmid=24548565|pmc=3996918 |doi=10.1016/j.febslet.2014.02.004|year=2014|bibcode=2014FEBSL.588.1379L }}</ref> This has led to the idea that pannexins may not form intercellular junctions in the same way connexins and innexins do and therefore should not use the same hemi-channel/channel naming.<ref>{{Cite journal |title=Pannexin channels are not gap junction hemichannels |journal=Channels |vauthors=Sosinsky GE, Boassa D, Dermietzel R, Duffy HS, Laird DW, MacVicar B, Naus CC, Penuela S, Scemes E, Spray DC, Thompson RJ, Zhao H, Dahl G |date=2011-05-01 |issue=3 |volume=5 |pages=193–197 |doi=10.4161/chan.5.3.15765 |pmid=21532340 |pmc=3704572 |doi-access=free}}</ref> Others have presented evidence based on genetic sequencing and overall functioning in tissues, that pannexins should still be considered part of the gap junction family of proteins despite structural differences. These researchers also note that there are still more groups of connexin [[orthologs]] to be discovered.<ref>{{Cite journal |title=Are there gap junctions without connexins or pannexins? |journal=BMC Ecol. Evol. |url= |last=Slivko-Koltchik |first=Georgy A. |date=2019-02-26 |issue=Suppl 1 |article-number=46 |volume=19 |doi=10.1186/s12862-019-1369-4|pmid=30813901 |pmc=6391747 |doi-access=free |bibcode=2019BMCEE..19S..46S }}</ref>

Gap junction channels formed from two identical hemichannels are called homotypic, while those with differing hemichannels are heterotypic. In turn, hemichannels of uniform protein composition are called [[homomeric]], while those with differing proteins are [[heteromeric]]. Channel composition influences the function of gap junction channels, and different connexins will not necessarily form heterotypic with all others.<ref name="partners">{{cite journal | last1=Hervé |first1=JC |last2= Bourmeyster |first2 = N | last3= Sarrouilhe |first3= D | last4= Duffy |first4 =HS |title= Gap junctional complexes: from partners to functions. |journal=Prog Biophys Mol Biol |date= May 2007|volume=94|issue=1–2 |pages=29–65 |doi= 10.1016/j.pbiomolbio.2007.03.010|pmid=17507078}}</ref>

Before innexins and connexins were well characterized, the genes coding for the connexin gap junction channels were classified in one of three groups (A, B and C; for example, {{Gene|GJA1}}, {{Gene|GJC1}}), based on gene mapping and [[sequence similarity]].<ref>{{cite journal|last1=Hsieh|first1=CL|last2=Kumar|first2=NM|last3=Gilula|first3=NB|last4=Francke|first4=U|title=Distribution of genes for gap junction membrane channel proteins on human and mouse chromosomes.|journal=Somatic Cell and Molecular Genetics|date=Mar 1991|volume=17|issue=2|pages=191–200|pmid=1849321|doi=10.1007/bf01232976|s2cid=44622463}}</ref><ref>{{cite journal|last1=Kumar|first1=NM|last2=Gilula|first2=NB|title=Molecular biology and genetics of gap junction channels.|journal=Seminars in Cell Biology|date=Feb 1992|volume=3|issue=1|pages=3–16|pmid=1320430|doi=10.1016/s1043-4682(10)80003-0}}</ref><ref>{{cite journal|last1=Kren|first1=BT|last2=Kumar|first2=NM|last3=Wang|first3=SQ|last4=Gilula|first4=NB|last5=Steer|first5=CJ|title=Differential regulation of multiple gap junction transcripts and proteins during rat liver regeneration.|journal=The Journal of Cell Biology|date=Nov 1993|volume=123|issue=3|pages=707–18|pmid=8227133|doi=10.1083/jcb.123.3.707|pmc=2200133}}</ref> However, connexin genes do not code directly for the expression of gap junction channels; genes can produce only the proteins that make up gap junction channels. An alternative naming system based on the protein's molecular weight is the most widely used (for example, connexin43=GJA1, connexin30.3=GJB4).

==Levels of organization==
In vertebrates, two pairs of six connexin proteins form a connexon. In invertebrates, six innexin proteins form an innexon. Otherwise, the structures are similar.
# The connexin genes (DNA) are transcribed to RNA, which is then translated to produce a connexin.
# One connexin protein has four [[transmembrane domain]]s<ref name="maeda" /><ref>{{cite journal |last1=Oshima |first1=A |last2=Tani |first2=K |last3=Fujiyoshi |first3=Y |title=Atomic structure of the innexin-6 gap junction channel determined by cryo-EM. |journal=Nat. Commun. |date=1 Dec 2016 |volume=7 |article-number=13681 |doi=10.1038/ncomms13681 |pmid=27905396|pmc=5146279 |bibcode=2016NatCo...713681O }}</ref>
# Six connexin proteins create one connexon channel a [[hemichannel]]. When identical connexin proteins join to form one connexon, it is called a homomeric connexon. When different connexin proteins join to form one connexon, it is called a heteromeric connexon.
# Two connexons, joined across a cell membrane, comprise a gap junction channel.<br />When two identical connexons come together to form a gap junction channel, it is called a homotypic channel. When one homomeric connexon and one heteromeric connexon come together, it is called a heterotypic gap junction channel. When two heteromeric connexons join, it is also called a heterotypic gap junction channel.
# Tens to thousands of gap junction channels cluster in areas to enable connexon pairs to form.<ref name=clusters>{{cite journal |last1=Lauf |first1=Undine |last2=Giepmans |first2=Ben N. G. |last3=Lopez |first3=Patricia |last4=Braconnot |first4=Sébastien |last5=Chen |first5=Shu-Chih |last6=Falk |first6=Matthias M. |title=Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells |journal=Proceedings of the National Academy of Sciences |date=6 August 2002 |volume=99 |issue=16 |pages=10446–10451 |doi=10.1073/pnas.162055899|pmid=12149451 |pmc=124935 |doi-access=free |bibcode=2002PNAS...9910446L }}</ref> The macromolecular complex is called a gap junction plaque. Molecules other than connexins are involved in gap junction plaques including [[tight junction protein 1]] and [[sodium channel]]s.<ref name="Connexin 43 gap junction plaque end"/><ref name="Localization of Na + channel cluste">{{cite journal |last1=Ivanovic |first1=Ena |last2=Kucera |first2=Jan P. |title=Localization of Na + channel clusters in narrowed perinexi of gap junctions enhances cardiac impulse transmission via ephaptic coupling: a model study |journal=The Journal of Physiology |date=November 2021 |volume=599 |issue=21 |pages=4779–4811 |doi=10.1113/JP282105|doi-access=free |pmid=34533834 |pmc=9293295 }}</ref>

==Properties of connexon pairs==
[[File:Validation of the dye diffusion assay performed with the flattened cochlear preparation.png|right|thumb|Light microscope images do not allow us to see connexons or innexons themselves but do let us see the fluorescing dye injected into one cell moving into neighboring cells when gap junctions are known to be present.<ref>{{cite journal |pmid=19116647 |doi=10.1371/journal.pone.0004088 |pmc=2605248 |volume=3 |issue=12 |title=Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice |year=2008 |journal=PLOS ONE |at=e4088 |editor1-last=Schiffmann |editor1-first=Raphael |last1=Chang |first1=Qing |last2=Tang |first2=Wenxue |last3=Ahmad |first3=Shoeb |last4=Zhou |first4=Binfei |last5=Lin |first5=Xi |bibcode=2008PLoSO...3.4088C |doi-access=free}}</ref>]]

A connexon or innexon channel pair:
# Allows for direct electrical communication between cells, although different hemichannel subunits can impart different single channel [[Electrical resistance and conductance|conductances]], from about 30 [[Siemens (unit)|pS]] to 500 pS.
# Allows for chemical communication between cells through the transmission of small [[second messenger]]s, such as inositol triphosphate ({{chem|link=Inositol trisphosphate|IP|3}}) and calcium ({{chem|link=Ca2+|Ca|2+}}),<ref name="mbc">{{Cite book|first=Bruce |last=Alberts |title=Molecular biology of the cell |publisher=Garland Science |location=New York |year=2002 |edition=4th |isbn=978-0-8153-3218-3}}{{Page needed|date=September 2010}}</ref> although different hemichannel subunits can impart different selectivities for particular molecules.
# Generally allows transmembrane movement of molecules smaller than 485 [[Dalton (unit)|daltons]]<ref>{{cite journal |vauthors= Hu X, Dahl G |year=1999 |title=Exchange of conductance and gating properties between gap junction hemichannels |journal=FEBS Lett |volume=451 |issue=2| pages=113–117 |doi=10.1016/S0014-5793(99)00558-X |pmid=10371149 |s2cid=19289550|doi-access=free |bibcode=1999FEBSL.451..113H }}</ref> (1,100 daltons through invertebrate gap junctions<ref>{{cite journal |vauthors=Loewenstein WR |title=Permeability of membrane junctions |journal=Ann. N. Y. Acad. Sci. |volume=137 |issue=2 |pages=441–472 |date=July 1966 |pmid=5229810 |bibcode=1966NYASA.137..441L |doi=10.1111/j.1749-6632.1966.tb50175.x|s2cid=22820528 }}</ref>), although different hemichannel subunits may impart different pore sizes and different charge selectivity. Large biomolecules, including [[nucleic acid]]s and [[protein]]s, are precluded from cytoplasmic transfer between cells through gap junction hemichannel pairs.
# Ensures that molecules and current passing through the gap junction do not leak into the intercellular space.

==Properties of connexons as hemichannels==
Unpaired connexons or innexons can act as hemichannels in a single membrane, allowing the cell to exchange molecules directly with the exterior of the cell. It has been shown that connexons would be available to do this prior to being incorporated into the gap junction plaques.<ref name="clusters"/> Some of the properties of these unpaired connexons are listed below:
#Pore or transmembrane channel size is highly variable, in the range of approximately 8-20Å in diameter.<ref>{{cite journal |last1=Khan |first1=Ali K. |last2=Jagielnicki |first2=Maciej |last3=Bennett |first3=Brad.C. |last4=Purdy |first4=Michael D. |last5=Yeager |first5=Mark |title=Cryo-EM structure of an open conformation of a gap junction hemichannel in lipid bilayer nanodiscs |journal=Structure |date=September 2021 |volume=29 |issue=9 |pages=1040–1047.e3 |doi=10.1016/j.str.2021.05.010|pmid=34129834 |pmc=9616683 }}</ref>
#They connect the cytoplasm of the cell to the cell exterior and are thought to be in a closed state by default in order to prevent leakage from the cell.<ref>{{cite journal |last1=Goodenough |first1=Daniel A. |last2=Paul |first2=David L. |title=Beyond the gap: functions of unpaired connexon channels |journal=Nature Reviews Molecular Cell Biology |date=April 2003 |volume=4 |issue=4 |pages=285–295 |doi=10.1038/nrm1072|pmid=12671651 |s2cid=18103080 }}</ref><ref>{{cite journal |last1=Laird |first1=Dale W. |last2=Lampe |first2=Paul D. |title=Therapeutic strategies targeting connexins |journal=Nature Reviews Drug Discovery |date=December 2018 |volume=17 |issue=12 |pages=905–921 |doi=10.1038/nrd.2018.138|pmid=30310236 |pmc=6461534 }}</ref>
#Some connexons respond to external factors by opening up. Mechanical shear and various diseases can cause this to happen.<ref name=hemichannel>{{cite journal |last1=Van Campenhout |first1=Raf |last2=Gomes |first2=Ana Rita |last3=De Groof |first3=Timo W.M. |last4=Muyldermans |first4=Serge |last5=Devoogdt |first5=Nick |last6=Vinken |first6=Mathieu |title=Mechanisms Underlying Connexin Hemichannel Activation in Disease |journal=International Journal of Molecular Sciences |date=28 March 2021 |volume=22 |issue=7 |page=3503 |doi=10.3390/ijms22073503|doi-access=free |pmid=33800706 |pmc=8036530 }}</ref>
Establishing further connexon properties different to those of connexon pairs, proves difficult due to separating their effects experimentally in organisms.<ref name="hemichannel" />

==Occurrence and distribution==
Gap junctions have been observed in various animal organs and tissues where cells contact each other. From the 1950s to 1970s they were detected in:

* Human islet of Langerhans,<ref>{{cite journal |vauthors=Orci L, Malaisse-Lagae F, Amherdt M, etal |date=November 1975 |title=Cell contacts in human islets of Langerhans |url=http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=1102552 |archive-url=https://archive.today/20130414164326/http://jcem.endojournals.org/cgi/pmidlookup?view=long&pmid=1102552 |archive-date=April 14, 2013 |journal=J. Clin. Endocrinol. Metab. |volume=41 |issue=5 |pages=841–4 |doi=10.1210/jcem-41-5-841 |pmid=1102552|url-access=subscription }}</ref> myometrium,<ref>{{cite journal |last1=Garfield |first1=RE |last2=Sims |first2=SM |last3=Kannan |first3=MS |last4=Daniel |first4=EE |date=November 1978 |title=Possible role of gap junctions in activation of myometrium during parturition |journal=Am. J. Physiol. |volume=235 |issue=5 |pages=C168–79 |doi=10.1152/ajpcell.1978.235.5.C168 |pmid=727239 |s2cid=31610495}}</ref> and eye lens<ref>{{cite journal |last1=Goodenough |first1=DA |date=November 1979 |title=Lens gap junctions: a structural hypothesis for nonregulated low-resistance intercellular pathways |journal=Invest. Ophthalmol. Vis. Sci. |volume=18 |issue=11 |pages=1104–22 |pmid=511455}}</ref>
* Rat pancreas, liver, adrenal cortex, epididymis, duodenum, muscle,<ref>{{cite journal |vauthors=Friend DS, Gilula NB |date=June 1972 |title=Variations in tight and gap junctions in mammalian tissues |journal=J. Cell Biol. |volume=53 |issue=3 |pages=758–76 |doi=10.1083/jcb.53.3.758 |pmc=2108762 |pmid=4337577}}</ref> and seminiferous tubules<ref>{{cite journal |vauthors=McGinley D, Posalaky Z, Provaznik M |date=October 1977 |title=Intercellular junctional complexes of the rat seminiferous tubules: a freeze-fracture study |journal=Anat. Rec. |volume=189 |issue=2 |pages=211–31 |doi=10.1002/ar.1091890208 |pmid=911045 |s2cid=19611753}}</ref>
* Rabbit cornea,<ref>{{cite journal |author=Kreutziger GO |date=September 1976 |title=Lateral membrane morphology and gap junction structure in rabbit corneal endothelium |journal=Exp. Eye Res. |volume=23 |issue=3 |pages=285–93 |doi=10.1016/0014-4835(76)90129-9 |pmid=976372}}</ref> ovary,<ref>{{cite journal |last1=Albertini |first1=DF |last2=Anderson |first2=E. |date=Oct 1974 |title=The appearance and structure of intercellular connections during the ontogeny of the rabbit ovarian follicle with particular reference to gap junctions |journal=J Cell Biol |volume=63 |issue=1 |pages=234–50 |doi=10.1083/jcb.63.1.234 |pmc=2109337 |pmid=4417791}}</ref> and skin<ref>{{cite journal |author=Prutkin L |date=February 1975 |title=Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, keratoacanthoma |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=1109802 |journal=Cancer Res. |volume=35 |issue=2 |pages=364–9 |pmid=1109802}}</ref>
* Monkey retina<ref>{{cite journal |last1=Raviola |first1=E |last2=Gilula |first2=NB |date=Jun 1973 |title=Gap junctions between photoreceptor cells in the vertebrate retina |journal=Proc Natl Acad Sci U S A |volume=70 |issue=6 |pages=1677–81 |bibcode=1973PNAS...70.1677R |doi=10.1073/pnas.70.6.1677 |pmc=433571 |pmid=4198274 |doi-access=free}}</ref>
* Chick embryos<ref>{{cite journal |last1=Bellairs |first1=R |last2=Breathnach |first2=AS |last3=Gross |first3=M |date=Sep 1975 |title=Freeze-fracture replication of junctional complexes in unincubated and incubated chick embryos |journal=Cell Tissue Res. |volume=162 |issue=2 |pages=235–52 |doi=10.1007/BF00209209 |pmid=1237352 |s2cid=38441429}}</ref>
* Frog embryos<ref name="ReferenceA">J. Cell Biol. 1974 Jul;62(1) 32-47.Assembly of gap junctions during amphibian neurulation. Decker RS, Friend DS.</ref>
* Fish [[blastoderm]]<ref>{{cite journal |vauthors=Lentz TL, Trinkaus JP |date=March 1971 |title=Differentiation of the junctional complex of surface cells in the developing Fundulus blastoderm |journal=J. Cell Biol. |volume=48 |issue=3 |pages=455–72 |doi=10.1083/jcb.48.3.455 |pmc=2108114 |pmid=5545331}}</ref>
* [[Crayfish]] nerves<ref name="robertson">{{cite journal |last1=Robertson |first1=JD |date=February 1953 |title=Ultrastructure of two invertebrate synapses |journal=Proceedings of the Society for Experimental Biology and Medicine |volume=82 |issue=2 |pages=219–23 |doi=10.3181/00379727-82-20071 |pmid=13037850 |s2cid=39294652}}</ref>
* [[Lamprey]] and [[tunicate]] heart<ref>{{cite journal |last1=Shibata |first1=Y |last2=Yamamoto |first2=T |date=March 1977 |title=Gap junctions in the cardiac muscle cells of the lamprey |journal=Cell Tissue Res. |volume=178 |issue=4 |pages=477–82 |doi=10.1007/BF00219569 |pmid=870202 |s2cid=21426059}}</ref><ref>{{cite journal |last1=Lorber |first1=V |last2=Rayns |first2=DG |date=April 1977 |title=Fine structure of the gap junction in the tunicate heart |journal=Cell Tissue Res. |volume=179 |issue=2 |pages=169–75 |doi=10.1007/BF00219794 |pmid=858161 |s2cid=21604678}}</ref>
* Goldfish and hamster pressure-sensing acoustico-vestibular receptors<ref>{{cite journal |vauthors=Hama K, Saito K |date=February 1977 |title=Gap junctions between the supporting cells in some acoustico-vestibular receptors |journal=J. Neurocytol. |volume=6 |issue=1 |pages=1–12 |doi=10.1007/BF01175410 |pmid=839246 |s2cid=30090247}}</ref>
* ''[[Daphnia]]'' [[hepatic caecum]]<ref>{{cite journal |last1=Hudspeth |first1=AJ |last2=Revel |first2=JP |date=Jul 1971 |title=Coexistence of gap and septate junctions in an invertebrate epithelium |journal=J. Cell Biol. |volume=50 |issue=1 |pages=92–101 |doi=10.1083/jcb.50.1.92 |pmc=2108432 |pmid=5563454}}</ref>
* [[Cephalopod]] digestive epithelium<ref>{{cite journal |last1=Boucaud-Camou |first1=Eve |year=1980 |title=Junctional structures in digestive epithelia of a cephalopod |journal=Tissue Cell |volume=12 |issue=2 |pages=395–404 |doi=10.1016/0040-8166(80)90013-0 |pmid=7414602}}</ref>
* [[Hydra (genus)|''Hydra'']] muscle<ref name="Hand72" />
* Cockroach hemocyte capsules<ref>{{cite journal |author=Baerwald RJ |year=1975 |title=Inverted gap and other cell junctions in cockroach hemocyte capsules: a thin section and freeze-fracture study |journal=Tissue Cell |volume=7 |issue=3 |pages=575–85 |doi=10.1016/0040-8166(75)90027-0 |pmid=1179417}}</ref>
* Reaggregated cells<ref>{{cite journal |vauthors=Johnson R, Hammer M, Sheridan J, Revel JP |date=November 1974 |title=Gap junction formation between reaggregated Novikoff hepatoma cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=71 |issue=11 |pages=4536–40 |bibcode=1974PNAS...71.4536J |doi=10.1073/pnas.71.11.4536 |pmc=433922 |pmid=4373716 |doi-access=free}}</ref><ref>{{cite journal |last1=Knudsen |first1=KA |last2=Horwitz |first2=AF |year=1978 |title=Toward a mechanism of myoblast fusion |journal=Prog Clin Biol Res |volume=23 |pages=563–8 |pmid=96453}}</ref>

Gap junctions have continued to be found in nearly all healthy animal cells that touch each other. Techniques such as [[confocal microscopy]] allow more rapid surveys of large areas of tissue. Tissues that were traditionally considered to have isolated cells such as in bone were shown to have cells that were still connected with gap junctions, however tenuously.<ref>{{cite journal |vauthors=Jones SJ, Gray C, Sakamaki H, etal |title=The incidence and size of gap junctions between the bone cells in rat calvaria |journal=Anat. Embryol. |volume=187 |issue=4 |pages=343–52 |date=April 1993 |pmid=8390141 |doi=10.1007/BF00185892 |s2cid=33191311 }}</ref> Exceptions to this are cells not normally in contact with neighboring cells, such as blood cells suspended in blood plasma. Adult skeletal muscle is a possible exception to the rule though their large size makes it difficult to be certain of this. An argument used against skeletal muscle gap junctions is that if they were present gap junctions may propagate contractions in an arbitrary way through cells making up the muscle. However, other muscle types do have gap junctions which do not cause arbitrary contractions.<ref>{{cite journal | pmid = 15679888 | doi=10.1186/1475-925X-4-7 | pmc=549032 | volume=4 | issue=1 | title=Gap-junction channels inhibit transverse propagation in cardiac muscle | year=2005 | journal=Biomed Eng Online | page=7 | last1 = Sperelakis | first1 = Nicholas | last2 = Ramasamy | first2 = Lakshminarayanan | doi-access=free }}</ref> Sometimes the number of gap junctions are reduced or absent in diseased tissues such as cancers<ref>{{cite journal |vauthors=Larsen WJ, Azarnia R, Loewenstein WR |title=Intercellular communication and tissue growth: IX. Junctional membrane structure of hybrids between communication-competent and communication-incompetent cells |journal=J. Membr. Biol. |volume=34 |issue=1 |pages=39–54 |date=June 1977 |pmid=561191 |doi=10.1007/BF01870292 |s2cid=2831462 }}</ref><ref>{{cite journal |vauthors=Corsaro CM, Migeon BR|title=Comparison of contact-mediated communication in normal and transformed human cells in culture |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=74 |issue=10 |pages=4476–80 |date=October 1977 |pmid=270694 |pmc=431966 |bibcode=1977PNAS...74.4476C |doi=10.1073/pnas.74.10.4476 |doi-access=free }}</ref><ref>{{cite journal | pmid = 11145599 | volume=142 | issue=1 | title=Developmental exposure to estrogens alters epithelial cell adhesion and gap junction proteins in the adult rat prostate |date=January 2001 | journal=Endocrinology | pages=359–69 | doi = 10.1210/endo.142.1.7893 | last1 = Habermann | first1 = H | last2 = Chang | first2 = WY | last3 = Birch | first3 = L | last4 = Mehta | first4 = P | last5 = Prins | first5 = GS| doi-access = free }}</ref> or the aging process.<ref>{{cite journal | pmid = 761600 | volume=119 | issue=1 | title=Development of the aging cell surface. Reduction of gap junction-mediated metabolic cooperation with progressive subcultivation of human embryo fibroblasts (IMR-90) |date=March 1979 | journal=Exp. Cell Res. | pages=127–43 | doi=10.1016/0014-4827(79)90342-2 | last1 = Kelley | first1 = Robert O. | last2 = Vogel | first2 = Kathryn G. | last3 = Crissman | first3 = Harry A. | last4 = Lujan | first4 = Christopher J. | last5 = Skipper | first5 = Betty E.}}</ref>

[[File:Cell pannexin tree.svg|thumb|Cell pannexin tree with white squares having communication proteins yet to be discovered]]Since the discovery of innexins, pannexins and unnexins, gaps in our knowledge of [[intercellular communication]] are becoming more defined. Innexins look and behave similarly to connexins and can be seen to fill a similar role to connexins in invertebrates. Pannexins also look individually similar to connexins though they do not appear to easily form gap junctions. Of the over 20 metazoan groups connexins have been found only in [[vertebrata]] and [[tunicata]]. Innexins and pannexins are far more widespread including innexin homologues in vertebrates.<ref>{{cite journal |last1=Phelan |first1=Pauline |title=Innexins: members of an evolutionarily conserved family of gap-junction proteins |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |date=June 2005 |volume=1711 |issue=2 |pages=225–245 |doi=10.1016/j.bbamem.2004.10.004|pmid=15921654 |doi-access=free }}</ref><ref>{{cite journal |last1=Hervé |first1=Jean-Claude |last2=Phelan |first2=Pauline |last3=Bruzzone |first3=Roberto |last4=White |first4=Thomas W. |title=Connexins, innexins and pannexins: Bridging the communication gap |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |date=December 2005 |volume=1719 |issue=1–2 |pages=3–5 |doi=10.1016/j.bbamem.2005.11.013|doi-access=free |pmid=16359939 }}</ref> The unicellular [[Trypanosomatida]]e parasites presumably have unnexin genes to aid in their infection of animals including humans.<ref>{{cite journal |last1=Güiza |first1=Juan |last2=García |first2=Aníbal |last3=Arriagada |first3=Javiera |last4=Gutiérrez |first4=Camila |last5=González |first5=Jorge |last6=Márquez-Miranda |first6=Valeria |last7=Alegría-Arcos |first7=Melissa |last8=Duarte |first8=Yorley |last9=Rojas |first9=Maximiliano |last10=González-Nilo |first10=Fernando |last11=Sáez |first11=Juan C. |last12=Vega |first12=José L. |title=Unnexins: Homologs of innexin proteins in Trypanosomatidae parasites |journal=Journal of Cellular Physiology |date=February 2022 |volume=237 |issue=2 |pages=1547–1560 |doi=10.1002/jcp.30626|pmid=34779505 |s2cid=244116450 }}</ref> The even smaller [[adenovirus]] has its own vinnexin,<ref>{{cite journal |last1=Turnbull |first1=Matthew W. |last2=Volkoff |first2=Anne-Nathalie |last3=Webb |first3=Bruce A. |last4=Phelan |first4=Pauline |title=Functional gap junction genes are encoded by insect viruses |journal=Current Biology |date=July 2005 |volume=15 |issue=13 |pages=R491–R492 |doi=10.1016/j.cub.2005.06.052|doi-access=free |pmid=16005277 |bibcode=2005CBio...15.R491T }}</ref> apparently derived from an innexin, to aid its transmission between the virus's insect hosts.

The term ''gap junction'' cannot be defined by a single protein or family of proteins with a specific function. For example, gap junction structures are found in [[porifera|sponges]], despite the absence of pannexins. While we are still at the early stages of understanding the nervous system of a sponge<ref>{{cite journal |last1=Moroz |first1=Leonid L. |last2=Romanova |first2=Daria Y. |title=Alternative neural systems: What is a neuron? (Ctenophores, sponges and placozoans) |journal=Frontiers in Cell and Developmental Biology |date=23 December 2022 |volume=10 |article-number=1071961 |doi=10.3389/fcell.2022.1071961|pmid=36619868 |pmc=9816575 |doi-access=free }}</ref> the ''gap junctions'' of sponges may as yet indicate intercellular communications pathways.<ref>{{cite journal |last1=Bergquist |first1=P.R. |last2=Green |first2=C.R. |title=An ultrastructural study of settlement and metamorphosis in sponge larvae |journal=Cah. Biol. Mar. |date=1977 |volume=18 |pages=289–302}}</ref><ref>{{cite journal |last1=Green |first1=C.R. |last2=Bergquist |first2=P.R. |title=Cell membrane specializations in the Porifera |journal=Coll Int Cent Natn Res Scient |date=1979 |volume=291 |pages=153–158}}</ref>

==Functions==
At least five discrete functions have been ascribed to [[gap junction protein]]s:
# Electrical and metabolic coupling between cells
# Electrical and metabolic exchange through hemichannels
# Tumor suppressor genes ([[GJA1|Cx43]], [[GJB1|Cx32]] and [[GJD2|Cx36]])
# Adhesive function independent of conductive gap junction channel (neural migration in neocortex)
# Role of carboxyl-terminal in [[Cell signaling|signaling cytoplasmic pathways]] (Cx43)

In a more general sense, gap junctions may be seen to function at the simplest level as a direct cell to cell pathway for electrical currents, small molecules and ions. The control of this communication allows complex downstream effects on multicellular organisms.

===Embryonic, organ and tissue development===
In the 1980s, more subtle roles of gap junctions in communication have been investigated. It was discovered that gap junction communication could be disrupted by adding anti-connexin antibodies into embryonic cells.<ref>{{cite journal | pmid = 6088995 | volume=311 | issue=5982 | title=Antibodies to gap-junctional protein selectively disrupt junctional communication in the early amphibian embryo | year=1984 | journal=Nature | pages=127–31 | bibcode = 1984Natur.311..127W | last1 = Warner | first1 = Anne E. | last2 = Guthrie | first2 = Sarah C. | last3 = Gilula | first3 = Norton B. | doi = 10.1038/311127a0| s2cid=2620476 }}</ref><ref>{{cite book | pmid = 3030673 | volume=125 | pages=154–67 | last1 = Warner | first1 = AE| title=Ciba Foundation Symposium 125 - Junctional Complexes of Epithelial Cells | chapter=The Use of Antibodies to Gap Junction Protein to Explore the Role of Gap Junctional Communication During Development | doi=10.1002/9780470513408.ch10 | series=Novartis Foundation Symposia | date=2007 | isbn=978-0-470-51340-8 }}</ref> Embryos with areas of blocked gap junctions failed to develop normally. The mechanism by which antibodies blocked the gap junctions was unclear; systematic studies were undertaken to elucidate the mechanism.<ref>{{cite journal | pmid = 8661989 | volume=150 | issue=3 | title=Effect of antipeptide antibodies directed against three domains of connexin43 on the gap junctional permeability of cultured heart cells |date=April 1996 | journal=J. Membr. Biol. | pages=243–53 | doi = 10.1007/s002329900048 | last1 = Bastide | first1 = B | last2 = Jarry-Guichard | first2 = T | last3 = Briand | first3 = JP | last4 = Délèze | first4 = J | last5 = Gros | first5 = D| s2cid=20408672 }}</ref><ref>{{cite journal | pmid = 9700496 | volume=24 | issue=1 | title=Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes |date=September 1998 | journal=Glia | pages=141–54 | doi = 10.1002/(SICI)1098-1136(199809)24:1<141::AID-GLIA13>3.0.CO;2-R | last1 = Hofer | first1 = A | last2 = Dermietzel | first2 = R| s2cid=23234120 }}</ref> Refinement of these studies suggested that gap junctions were key in the development of cell polarity<ref name="ReferenceB">{{cite journal |vauthors=Francis R, Xu X, Park H|title=Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics |journal=PLOS ONE |volume=6 |issue=10 |article-number=e26379 |year=2011 |pmid=22022608 |pmc=3194834 |doi=10.1371/journal.pone.0026379 |editor1-last=Brandner |editor1-first=Johanna M|bibcode = 2011PLoSO...626379F |display-authors=etal|doi-access=free }}</ref> and the left-right symmetry in animals.<ref>{{cite journal | pmid = 9806775 | doi=10.1006/dbio.1998.9024 | volume=203 | issue=1 | title=Gap junctions are involved in the early generation of left-right asymmetry |date=November 1998 | journal=Dev. Biol. | pages=90–105 | last1 = Levin | first1 = Michael | last2 = Mercola | first2 = Mark| citeseerx=10.1.1.137.4340 }}</ref><ref>{{cite journal | pmid = 10518488 | volume=126 | issue=21 | title=Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node |date=November 1999 | journal=Development | pages=4703–14 | last1 = Levin | first1 = M | last2 = Mercola | first2 = M| doi=10.1242/dev.126.21.4703 }}</ref> While signaling that determines the position of body organs appears to rely on gap junctions, so does the more fundamental differentiation of cells at later stages of embryonic development.<ref>{{cite journal | pmid = 10079512 | doi=10.1002/(SICI)1520-6408(1999)24:1/2<69::AID-DVG8>3.0.CO;2-M | volume=24 | issue=1–2 | title=Gap junction blockage interferes with neuronal and astroglial differentiation of mouse P19 embryonal carcinoma cells | year=1999 | journal=Dev. Genet. | pages=69–81 | last1 = Bani-Yaghoub | first1 = Mahmud | last2 = Underhill | first2 = T. Michael | last3 = Naus | first3 = Christian C.G.}}</ref><ref>{{cite journal | pmid = 10192774 | doi=10.1006/exnr.1998.6950 | volume=156 | issue=1 | title=The effects of gap junction blockage on neuronal differentiation of human NTera2/clone D1 cells |date=March 1999 | journal=Exp. Neurol. | pages=16–32 | last1 = Bani-Yaghoub | first1 = Mahmud | last2 = Bechberger | first2 = John F. | last3 = Underhill | first3 = T. Michael | last4 = Naus | first4 = Christian C. G.| s2cid=41420671}}</ref><ref>{{cite journal | pmid = 10666026 | volume=278 | issue=2 | title=Differentiation of human fetal osteoblastic cells and gap junctional intercellular communication |date=February 2000 | journal=Am. J. Physiol., Cell Physiol. | pages=C315–22 | last1 = Donahue | first1 = HJ | last2 = Li | first2 = Z | last3 = Zhou | first3 = Z | last4 = Yellowley | first4 = CE| doi=10.1152/ajpcell.2000.278.2.C315 | s2cid=9894657 }}</ref><ref>{{cite journal | pmid = 12826585 | doi=10.1095/biolreprod.103.016360 | volume=69 | issue=5 | title=Requirement of gap junctional intercellular communication for human villous trophoblast differentiation |date=November 2003 | journal=Biol. Reprod. | pages=1472–80 | last1 = Cronier | first1 = L | last2 = Frendo | first2 = JL | last3 = Defamie | first3 = N | last4 = Pidoux | first4 = G | last5 = Bertin | first5 = G | last6 = Guibourdenche | first6 = J | last7 = Pointis | first7 = G | last8 = Malassine | first8 = A| doi-access = free}}</ref><ref>{{cite journal | pmid = 12893812 | doi=10.1242/jcs.00656 | volume=116 | issue=Pt 17 | title=ECM-induced gap junctional communication enhances mammary epithelial cell differentiation |date=September 2003 | journal=J. Cell Sci. | pages=3531–41 | last1 = El-Sabban | first1 = ME | last2 = Sfeir | first2 = AJ | last3 = Daher | first3 = MH | last4 = Kalaany | first4 = NY | last5 = Bassam | first5 = RA | last6 = Talhouk | first6 = RS| doi-access = | s2cid=5057466 }}</ref>

Gap junctions were found to be responsible for the transmission of signals required for drugs to have an effect.<ref>{{cite journal | pmid = 10523421 | pmc=2269589 | volume=520 | title=The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication |date=October 1999 | journal=J. Physiol. | pages=539–50 | issue=2 | doi = 10.1111/j.1469-7793.1999.00539.x | last1 = Chaytor | first1 = AT | last2 = Martin | first2 = PE | last3 = Evans | first3 = WH | last4 = Randall | first4 = MD | last5 = Griffith | first5 = TM}}</ref> Conversely, some drugs were shown to block gap junction channels.<ref>{{cite journal | pmid = 11535816 | doi=10.1073/pnas.191206198 | pmc=58578 | volume=98 | issue=19 | title=Quinine blocks specific gap junction channel subtypes |date=September 2001 | journal=Proc. Natl. Acad. Sci. U.S.A. | pages=10942–7 | last1 = Srinivas | first1 = M | last2 = Hopperstad | first2 = MG | last3 = Spray | first3 = DC|bibcode = 2001PNAS...9810942S | doi-access=free }}</ref>

===The bystander effect and disease===

====Cell death====
The ''bystander effect'' has its connotations of the innocent bystander being killed. When cells are dying or compromised due to disease or injury, messages are transmitted to neighboring cells by gap junctions. This can cause otherwise healthy bystander cells to also die.<ref>{{cite journal | pmid = 8186287 | doi=10.1089/hum.1993.4.6-725 | volume=4 | issue=6 | title=In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy |date=December 1993 | journal=Hum. Gene Ther. | pages=725–31 | last1 = Li Bi | first1 = Wan | last2 = Parysek | first2 = Linda M. | last3 = Warnick | first3 = Ronald | last4 = Stambrook | first4 = Peter J.}}</ref> 

The [[Bystander effect (radiobiology)|bystander effect]] was later researched with regard to cells damaged by radiation or mechanical injury and in turn wound healing.<ref>{{cite journal | pmid = 12194273 | volume=99 | issue=1–4 | title=Bystander effects: intercellular transmission of radiation damage signals | year=2002 | journal=Radiat Prot Dosimetry | pages=159–62 | doi = 10.1093/oxfordjournals.rpd.a006751 | last1 = Little | first1 = JB | last2 = Azzam | first2 = EI | last3 = De Toledo | first3 = SM | last4 = Nagasawa | first4 = H}}</ref><ref>{{cite journal | pmid = 12194291 | volume=99 | issue=1–4 | title=Genotoxic damage in non-irradiated cells: contribution from the bystander effect | year=2002 | journal=Radiat Prot Dosimetry | pages=227–32 | doi = 10.1093/oxfordjournals.rpd.a006769 | last1 = Zhou | first1 = H | last2 = Randers-Pehrson | first2 = G | last3 = Suzuki | first3 = M | last4 = Waldren | first4 = CA | last5 = Hei | first5 = TK}}</ref><ref>{{cite journal | pmid = 12556327 | volume=79 | issue=1 | title=Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review |date=January 2003 | journal=Int. J. Radiat. Biol. | pages=15–25 | last1 = Lorimore | first1 = SA | last2 = Wright | first2 = EG | doi=10.1080/0955300021000045664| s2cid=44821116 }}</ref><ref>{{cite journal | pmid = 14617290 | volume=11 | issue=6 | title=Role for gap junctional intercellular communications in wound repair | year=2003 | journal=Wound Repair Regen | pages=481–9 | doi = 10.1046/j.1524-475X.2003.11616.x | last1 = Ehrlich | first1 = HP | last2 = Diez | first2 = T| s2cid=25113646 }}</ref><ref>{{cite journal | pmid = 15927148 | doi=10.1016/j.bjps.2004.12.022 | volume=58 | issue=5 | title=Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury |date=July 2005 | journal=Br J Plast Surg | pages=658–67 | last1 = Coutinho | first1 = P. | last2 = Qiu | first2 = C. | last3 = Frank | first3 = S. | last4 = Wang | first4 = C.M. | last5 = Brown | first5 = T. | last6 = Green | first6 = C.R. | last7 = Becker | first7 = D.L.| doi-access = free }}</ref> Disease seems to have an effect on the ability of gap junctions to fulfill their roles in wound healing.<ref>{{cite journal | pmid = 17717278 | doi=10.2337/db07-0613 | volume=56 | issue=11 | title=Abnormal connexin expression underlies delayed wound healing in diabetic skin |date=November 2007 | journal=Diabetes | pages=2809–17 | last1 = Wang | first1 = C. M. | last2 = Lincoln | first2 = J. | last3 = Cook | first3 = J. E. | last4 = Becker | first4 = D. L.| doi-access = free}}</ref><ref>{{cite journal | pmid = 9550065 | volume=9 | issue=1 | title=Considerations for the aesthetic restoration of endodontically treated anterior teeth following intracoronal bleaching | year=1997 | journal=Pract Periodontics Aesthet Dent | pages=117–28 | last1 = Rivera | first1 = EM | last2 = Vargas | first2 = M | last3 = Ricks-Williamson | first3 = L}}</ref> The oral administration of gap junction blockers to reduce the symptoms of disease in remote parts of the body is slowly becoming a reality.<ref>{{cite journal |last1=Mugisho |first1=Odunayo O. |last2=Aryal |first2=Jyoti |last3=Shorne |first3=Avik |last4=Lyon |first4=Heather |last5=Acosta |first5=Monica L. |last6=Green |first6=Colin R. |last7=Rupenthal |first7=Ilva D. |title=Orally Delivered Connexin43 Hemichannel Blocker, Tonabersat, Inhibits Vascular Breakdown and Inflammasome Activation in a Mouse Model of Diabetic Retinopathy |journal=International Journal of Molecular Sciences |date=15 February 2023 |volume=24 |issue=4 |page=3876 |doi=10.3390/ijms24043876|pmid=36835288 |pmc=9961562 |doi-access=free }}</ref>

====Tissue restructuring====
While there has been a tendency to focus on the bystander effect in disease due to the possibility of therapeutic avenues, there is evidence that there is a more central role in normal development of tissues. Death of some cells and their surrounding matrix may be required for a tissue to reach its final configuration; gap junctions appear essential to this process.<ref>{{cite journal | pmid = 12878681 | pmc=6740641 | volume=23 | issue=16 | title=Gap junctions mediate bystander cell death in developing retina |date=July 2003 | journal=J. Neurosci. | pages=6413–22 | last1 = Cusato | first1 = K | last2 = Bosco | first2 = A | last3 = Rozental | first3 = R | last4 = Guimarães | first4 = CA | last5 = Reese | first5 = BE | last6 = Linden | first6 = R | last7 = Spray | first7 = DC| doi=10.1523/JNEUROSCI.23-16-06413.2003 }}</ref><ref>{{cite journal | pmid = 15225205 | doi=10.1111/j.1067-1927.2004.012310.x | volume=12 | issue=3 | title=Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication | year=2004 | journal=Wound Repair Regen | pages=269–75 | last1 = Moyer | first1 = Kurtis E. | last2 = Saggers | first2 = Gregory C. | last3 = Ehrlich | first3 = H. Paul| s2cid=24363587 }}</ref> There are also more complex studies that try to combine our understanding of the simultaneous roles of gap junctions in both wound healing and tissue development.<ref>{{cite journal | pmid = 16628254 | doi=10.1172/JCI27186 | pmc=1440704 | volume=116 | issue=5 | title=Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response |date=May 2006 | journal=J. Clin. Invest. | pages=1243–53 | last1 = Djalilian | first1 = A. R. | last2 = McGaughey | first2 = D | last3 = Patel | first3 = S | last4 = Seo | first4 = EY | last5 = Yang | first5 = C | last6 = Cheng | first6 = J | last7 = Tomic | first7 = M | last8 = Sinha | first8 = S | last9 = Ishida-Yamamoto | first9 = A| last10=Segre | first10=J. A. | display-authors=8 }}</ref><ref>{{cite journal | pmid = 19966054 | doi=10.1152/ajpheart.00806.2009 | pmc=2822575 | volume=298 | issue=2 | title=Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling |date=February 2010 | journal=Am. J. Physiol. Heart Circ. Physiol. | pages=H477–87 | last1 = Zhang | first1 = Y. | last2 = Wang | first2 = H. | last3 = Kovacs | first3 = A. | last4 = Kanter | first4 = E. M. | last5 = Yamada | first5 = K. A.}}</ref><ref>{{cite journal | vauthors = Ey B, Eyking A, Gerken G, Podolsky DK, Cario E | title = TLR2 mediates gap junctional intercellular communication through connexin-43 in intestinal epithelial barrier injury | journal = J. Biol. Chem. | volume = 284 | issue = 33 | pages = 22332–43 | date = August 2009 | pmid = 19528242 | doi = 10.1074/jbc.M901619200 | pmc=2755956| doi-access = free }}</ref>

====Disease====
Mutations in connexins have been associated with many diseases in humans, including [[deafness]],<ref>{{cite journal |last1=Xu |first1=Ji |last2=Nicholson |first2=Bruce J. |title=The role of connexins in ear and skin physiology — Functional insights from disease-associated mutations |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |date=January 2013 |volume=1828 |issue=1 |pages=167–178 |doi=10.1016/j.bbamem.2012.06.024|pmid=22796187 |pmc=3521577 }}</ref> heart [[atrial fibrillation]] (standstill) and [[cataract]]s. The study of these mutations has helped clarify some of the functions of connexins.<ref>{{cite journal |last1=Srinivas |first1=Miduturu |last2=Verselis |first2=Vytas K. |last3=White |first3=Thomas W. |title=Human diseases associated with connexin mutations |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |date=1 January 2018 |volume=1860 |issue=1 |pages=192–201 |doi=10.1016/j.bbamem.2017.04.024|pmid=28457858 |pmc=5659969 }}</ref><ref>{{Cite journal|pmid=10099690 |year=1999 |first1=Thomas W. |last1=White |first2=David L. |last2=Paul |title=Genetic diseases and gene knockouts reveal diverse connexin functions |volume=61 |pages=283–310 |doi=10.1146/annurev.physiol.61.1.283 |journal=Annual Review of Physiology |issue=1}}</ref>

Hemichannels are thought to play a general role in the progression and severity of many diseases; this is in part due to hemichannels being an open door to the outside of each cell.<ref name="hemichannel"/>

===Areas of electrical coupling===
Gap junctions electrically couple cells throughout the body of most animals. Electrical coupling can be relatively fast acting and can be used over short distances within an organism. Tissues in this section have well known functions observed to be coordinated by gap junctions, with intercellular signaling happening in time frames of microseconds or less.

====Heart====
[[File:Perinexial ephaptic coupling.jpg|thumb|Effects of perinexal width on ephaptic coupling, for G gap = 0 nS]]Gap junctions are particularly important in [[cardiac muscle]]: the signal to contract is passed efficiently through gap junctions, allowing the heart muscle cells to contract in unison. The importance is emphasized by a secondary [[Ephaptic coupling|ephaptic pathway]] for the signal to contract also being associated with the gap junction plaques. This redundancy in signal transmission associated with gap junction plaques is the first to be described and involves sodium channels rather than connexins.<ref name="Localization of Na + channel cluste"/><ref>{{cite journal |last1=Ivanovic |first1=Ena |last2=Kucera |first2=Jan P. |title=Tortuous Cardiac Intercalated Discs Modulate Ephaptic Coupling |journal=Cells |date=2 November 2022 |volume=11 |issue=21 |page=3477 |doi=10.3390/cells11213477|doi-access=free |pmid=36359872 |pmc=9655400 }}</ref>

====Eye lens====
[[File:Lens3Dmap with txt.jpg|thumb|Eye lens showing arrangement of fiber cells with photos of gap junction plaques from different regions]]Precise control of light refraction, structural dimensions and transparency are key aspects of the eye lens structure that allow focusing by the eye. Transparency is aided by the absence of nerves and blood vessels from the lens, so gap junctions are left with a larger loading of intercellular communication than in other tissues reflected in large numbers of gap junctions. The [[crystallinity]] of the lens also means the cells and gap junctions are well ordered for systematic mapping of where the gap junction plaques are. As no cells are lost from the lens interior during the life of the animal, a complete map of the gap junctions is possible.<ref name = Gruijters>{{cite journal |last1=Gruijters |first1=W.T. |last2=Kistler |first2=J. |last3=Bullivant |first3=S. |title=Formation, distribution and dissociation of intercellular junctions in the lens |journal=Journal of Cell Science |date=1 October 1987 |volume=88 |issue=3 |pages=351–359 |doi=10.1242/jcs.88.3.351|pmid=3448099 }}</ref>

The associated figure shows how the size, shape, and frequency of gap junction plaques change with cell growth. With growth, fiber cells are progressively isolated from more direct metabolite exchange with the [[Aqueous humour|aqueous humor]] through the capsule and lens epithelium. The isolation correlates with the classical circular shape of larger plaques shown in the yellow zone being disrupted. Changing the fiber cells' morphology requires the movements of vesicles through the gap junction plaques at higher frequencies in this area.<ref name="Gruijters-vesicles">{{cite journal |last1=Gruijters |first1=W |title=Are gap junction membrane plaques implicated in intercellular vesicle transfer? |journal=Cell Biology International |date=2003 |volume=27 |issue=9 |pages=711–717 |doi=10.1186/s12862-019-1369-4|pmid=30813901 |pmc=6391747 |doi-access=free |bibcode=2019BMCEE..19S..46S }}</ref>

====Neurons====
A gap junction located between neurons is often referred to as an [[electrical synapse]]. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. In mammals, electrical synapses are present throughout the central nervous system and have been studied specifically in the [[neocortex]], [[hippocampus]], [[vestibular nucleus]], [[thalamic reticular nucleus]], [[locus coeruleus]], [[inferior olivary nucleus]], mesencephalic nucleus of the [[trigeminal nerve]], [[ventral tegmental area]], [[olfactory bulb]], [[retina]] and [[spinal cord]] of [[vertebrate]]s.<ref>{{cite journal | last1 = Connors | last2 = Long | year = 2004 | title = Electrical synapses in the mammalian brain | url = https://zenodo.org/record/894386| journal = Annu Rev Neurosci | volume = 27 | pages = 393–418 | doi=10.1146/annurev.neuro.26.041002.131128 | pmid=15217338}}<!--https://zenodo.org/record/894386--></ref>  In invertebrates, gap junctions are known to be expressed widely in the brain of the fruit fly, ''Drosophila''.<ref name="Ammer">{{cite journal 
  |title=Anatomical distribution and functional roles of electrical synapses in Drosophila
  |last1=Ammer |first1=Georg |last2=Vieira |first2=Renee M |last3=Fendl |first3=Sandra |last4=Borst |first4=Alexander
  |journal=Current Biology
  |volume=32
  |issue=9
  |year=2022
  |pages=2022–2036.e4 |publisher=Elsevier|doi=10.1016/j.cub.2022.03.040 |pmid=35385694 |bibcode=2022CBio...32E2022A |doi-access=free }}</ref>

There has been some observation of coupling in the [[locus coeruleus]] between weak neurons and [[glial cell]]s and in the [[cerebellum]] between [[Purkinje neuron]]s and [[Bergmann glial cell]]s. It appears that [[astrocyte]]s are coupled by gap junctions, both to other astrocytes and to [[oligodendrocyte]]s.<ref>{{cite journal|last=Orthmann-Murphy|first=Jennifer L.|author2=Abrams, Charles K. |author3=Scherer, Steven S. |title=Gap Junctions Couple Astrocytes and Oligodendrocytes|journal=Journal of Molecular Neuroscience|date=May 2008|volume=35|issue=1|pages=101–116|doi=10.1007/s12031-007-9027-5|pmid=18236012 |pmc=2650399}}</ref> Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in [[Pelizaeus–Merzbacher disease]] and [[multiple sclerosis]].

Connexin proteins expressed in neuronal gap junctions include m[[GJD2|CX36]], mCX57, and m[[GJC1|CX45]], with mRNAs for at least five other connexins (m[[GJB2|Cx26]], m[[GJC3|Cx30.2]], m[[GJB1|Cx32]], m[[GJA1|Cx43]], m[[GJC2|Cx47]]) detected but without immunocytochemical evidence for the corresponding protein within ultrastructurally defined gap junctions. Those mRNAs appear to be downregulated or destroyed by micro interfering RNAs ([[miRNA]]s) that are cell-type and cell-lineage specific.

Within the brain of the fruit fly ''Drosophila'', gap junctions are known to be critical for a variety of functions.<ref>{{cite journal 
  |title=Heterotypic gap junctions between two neurons in the Drosophila brain are critical for memory
  |last1= Wu |first1= Chia-Lin |last2= Shih |first2= Meng-Fu Maxwell |last3= Lai |first3= Jason Sih-Yu
  |last4= Yang |first4= Hsun-Ti |last5= Turner |first5= Glenn C |last6= Chen |first6= Linyi
  |last7= Chiang |first7= Ann-Shyn
  |journal=Current Biology
  |volume=21
  |issue=10
  |pages=848–854
  |year=2011
  |publisher=Elsevier  |doi= 10.1016/j.cub.2011.02.041 |pmid= 21530256 |bibcode= 2011CBio...21..848W }}</ref>
<ref name="Ammer"/>
<ref>{{cite journal 
  |title=Gap junction networks in mushroom bodies participate in visual learning and memory in Drosophila
  |last1=Liu |first1=Qingqing |last2=Yang |first2=Xing |last3=Tian |first3=Jingsong  |last4=Gao |first4=Zhongbao
  |last5=Wang |first5=Meng |last6=Li |first6=Yan |last7=Guo |first7=Aike
  |journal=eLife
  |volume=5
  |article-number=e13238
  |year=2016
  |url=https://elifesciences.org/articles/13238.pdf
  |publisher=eLife Sciences Publications, Ltd |doi=10.7554/eLife.13238 |doi-access=free |pmid=27218450 |pmc=4909397 }}</ref>

'''Astrocytes'''

An important feature of astrocytes is their high expression levels of the gap junction proteins [[connexin 30]] (Cx30) and [[connexin 43]] (Cx43). These proteins play crucial roles in regulating brain homeostasis through potassium buffering, intercellular communication, and nutrient transport.<ref>{{Cite journal |last1=Pannasch |first1=Ulrike |last2=Vargová |first2=Lydia |last3=Reingruber |first3=Jürgen |last4=Ezan |first4=Pascal |last5=Holcman |first5=David |last6=Giaume |first6=Christian |last7=Syková |first7=Eva |last8=Rouach |first8=Nathalie |date=2011-05-17 |title=Astroglial networks scale synaptic activity and plasticity |journal=Proceedings of the National Academy of Sciences |language=en |volume=108 |issue=20 |pages=8467–8472 |doi=10.1073/pnas.1016650108 |doi-access=free |issn=0027-8424 |pmc=3100942 |pmid=21536893|bibcode=2011PNAS..108.8467P }}</ref> Connexins typically form gap junction channels that allow direct intercellular communication between astrocytes. However, they can also form hemichannels that facilitate the exchange of ions and molecules with the extracellular space.

Studies have highlighted channel-independent functions of connexins, involving intracellular signaling, protein interactions, and cell adhesion.<ref>{{Cite journal |last1=Ghézali |first1=Grégory |last2=Dallérac |first2=Glenn |last3=Rouach |first3=Nathalie |date=2016 |title=Perisynaptic astroglial processes: dynamic processors of neuronal information |url=http://link.springer.com/10.1007/s00429-015-1070-3 |journal=Brain Structure and Function |language=en |volume=221 |issue=5 |pages=2427–2442 |doi=10.1007/s00429-015-1070-3 |pmid=26026482 |issn=1863-2653}}</ref> Specifically, Cx30 has been shown to regulate the insertion of astroglial processes into synaptic clefts, which controls the efficacy of glutamate clearance. This, in turn, affects the synaptic strength and long-term plasticity of excitatory terminals, indicating a significant role in modulating synaptic transmission. Levels of Cx30 regulate synaptic glutamate concentration, hippocampal excitatory synaptic strength, plasticity, and memory. Astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.<ref>{{Cite journal |last1=Hardy |first1=Eléonore |last2=Moulard |first2=Julien |last3=Walter |first3=Augustin |last4=Ezan |first4=Pascal |last5=Bemelmans |first5=Alexis-Pierre |last6=Mouthon |first6=Franck |last7=Charvériat |first7=Mathieu |last8=Rouach |first8=Nathalie |last9=Rancillac |first9=Armelle |date=2023-04-11 |editor-last=Eroglu |editor-first=Cagla |title=Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory |journal=PLOS Biology |language=en |volume=21 |issue=4 |article-number=e3002075 |doi=10.1371/journal.pbio.3002075 |doi-access=free |issn=1545-7885 |pmc=10089355 |pmid=37040348 |quote=Cx30 upregulation increases the connectivity of astroglial networks, it decreases spontaneous and evoked synaptic transmission. This effect results from a reduced neuronal excitability and translates into an alteration in the induction of synaptic plasticity and an in vivo impairment in learning processes. Altogether, these results suggest that astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.}}</ref>

Cx30 is not limited to regulating excitatory synaptic transmission but also plays a crucial role in inhibitory synaptic regulation and broader neuronal network activities.<ref>{{Cite journal |last1=Hardy |first1=Eléonore |last2=Cohen-Salmon |first2=Martine |last3=Rouach |first3=Nathalie |last4=Rancillac |first4=Armelle |date=September 2021 |title=Astroglial Cx30 differentially impacts synaptic activity from hippocampal principal cells and interneurons |url=https://onlinelibrary.wiley.com/doi/10.1002/glia.24017 |journal=Glia |language=en |volume=69 |issue=9 |pages=2178–2198 |doi=10.1002/glia.24017 |pmid=33973274 |issn=0894-1491 |quote=Cx30 differentially alters the electrophysiological and morphological properties of hippocampal cell populations. They modulates both excitatory and inhibitory inputs. Astrocytes, via Cx30, are thus active modulators of both excitatory and inhibitory synapses in the hippocampus.}}</ref> This highlights the importance of connexins in maintaining the intricate balance required for proper brain function.

====Retina====
Neurons within the [[retina]] show extensive coupling, both within populations of one cell type and between different cell types.<ref>{{cite journal |author1=Béla Völgyi |author2=Stewart A. Bloomfield |title=The diverse functional roles and regulation of neuronal gap junctions in the retina |journal=Nature Reviews Neuroscience |date=February 2009| volume=10 |issue=7 |pages=495–506| doi=10.1016/S0165-0173(99)00070-3 |pmid=19491906 |pmc=3381350}}</ref>

====Uterus====
The [[Uterus|uterine]] muscle ([[myometrium]]) remains in a quiescent relaxed state during [[pregnancy]] to maintain [[fetal development]]. Immediately preceding [[Childbirth|labor]], the myometrium transforms into an activated contractile unit by increasing expression of [[GJA1|connexin-43]] ([[Cx43|CX43]], a.k.a. Gap Junction Alpha-1 protein, [[GJA1]]) facilitating gap junction (GJ) formation between individual myometrial cells. Importantly, the formation of GJs promotes communication between neighbouring [[Muscle cell|myocytes]], which facilitates the transfer of small molecules such as secondary messengers, metabolites, and small ions for electrical coupling. Consistent with all species, uterine myometrial contractions propagate from spontaneous [[action potential]]s as a result of sudden change in [[Cell membrane|plasma membrane]] permeability. This leads to an increase of intracellular [[Ca²⁺]] concentration, facilitating action potential propagation through electrically coupled cells.<ref>Garfield, RE; Sims, SM; Kannan, MS; Daniel, EE (November 1978). "Possible role of gap junctions in activation of myometrium during parturition". ''Am. J. Physiol''. '''235''' (5): C168–79. [https://journals.physiology.org/doi/abs/10.1152/ajpcell.1978.235.5.C168 doi:10.1152/ajpcell.1978.235.5.C168]. PMID 727239. S2CID [https://www.semanticscholar.org/paper/Possible-role-of-gap-junctions-in-activation-of-Garfield-Sims/ce78aa441efb2f15ff4749d082197ed4db1b2584 31610495]</ref> It has more recently been discovered that uterine [[macrophage]]s directly physically couples with uterine myocytes through CX43, transferring Ca²⁺, to promote uterine muscle contraction and excitation during labor onset.<ref>Boros-Rausch, A., Shynlova, O., & Lye, S. J. (2021). "A Broad-Spectrum Chemokine Inhibitor Blocks Inflammation-Induced Myometrial Myocyte-Macrophage Crosstalk and Myometrial Contraction". ''Cells''. '''11''' (1): 128. [https://www.mdpi.com/2073-4409/11/1/128 doi: 10.3390/cells11010128] PMID 35011690</ref>

===Hemichannel function===
{{Multiple image
| image1            = Epithelium Cx50.jpg
| caption1          = Lens epithelial cells with gap junctions and hemichannels at the interface with fiber cells.
| image2            = Fiber ends Cx50-1.jpg
| caption2          = Lens fiber cells ends with gap junctions and hemichannels at the interface with fiber cells.
}}
Hemichannels contribute to a cellular network of gap junctions and allow the release of [[adenosine triphosphate]], [[glutamate]], [[Nicotinamide adenine dinucleotide]], and [[prostaglandin E2]] from cells, which can all act as messengers to cells otherwise disconnected from such messaging.<ref>{{cite journal |last1=Evans |first1=W. Howard |last2=De Vuyst |first2=Elke |last3=Leybaert |first3=Luc |title=The gap junction cellular internet: connexin hemichannels enter the signalling limelight |journal=Biochemical Journal |date=1 July 2006 |volume=397 |issue=1 |pages=1–14 |doi=10.1042/BJ20060175|pmid=16761954 |pmc=1479757 }}</ref> In this sense, a gap junction plaque forms a one-to-one relationship with the neighboring cell, daisy chaining many cells together. Hemichannels form a one to many relationship with the surrounding tissue.

On a larger scale, the one-to-many communication of cells is typically carried out by the vascular and nervous systems. This makes detecting the contribution of hemichannels to extracellular communication more difficult in whole organisms. With the eye lens, the vascular and nervous systems are absent, making reliance on hemichannels greater and their detection easier. At the interface of the lens with the aqueous humor (where the lens exchanges metabolites), both gap junction plaques and more diffused connexon distribution can be seen in the accompanying micrographs.

==Discovery==
===Form to function===
Well before the demonstration of the gap in gap junctions, they were seen at the junction of neighboring nerve cells. The close proximity of the neighboring cell membranes at the gap junction led researchers to speculate that they had a role in intercellular communication, in particular the transmission of electrical signals.<ref name="robertson" /><ref>{{Cite book|editor1-first=Michael |editor1-last=Locke |year=1963 |title=Cellular membranes in development |publisher=Academic Press |location=New York |oclc=261587041 |last1=Robertson |first1=J. D. }}{{Page needed|date=September 2010}}</ref><ref>{{Cite journal|pmid=7033238 |pmc=2112820 |title=Membrane structure |journal=The Journal of Cell Biology |year=1981 |volume=91 |issue=3 |author=Robertson |pages=189s–204s |jstor=1609517 |doi=10.1083/jcb.91.3.189s}}</ref> Gap junctions were also found to be electrically rectifying in the early studies and referred to as an [[electrical synapse]]<ref>{{Cite journal|doi=10.1038/180342a0 |title=Mechanism of Nerve-Impulse Transmission at a Crayfish Synapse |year=1957 |vauthors=Furshpan EJ, Potter DD |journal=Nature |volume=180 |pages=342–343 |pmid=13464833 |issue=4581 |bibcode=1957Natur.180..342F |s2cid=4216387}}</ref><ref>{{Cite journal |pmid=13642302 |pmc=1356828 |year=1959 |vauthors=Furshpan EJ, Potter DD |title=Transmission at the giant motor synapses of the crayfish |volume=145 |issue=2 |pages=289–325 |journal=The Journal of Physiology |doi=10.1113/jphysiol.1959.sp006143}}</ref> but are now known to be bidirectional in general.<ref name=":1">{{Cite book |title=Neuroscience |date=2001 |publisher=Sinauer Associates |isbn=978-0-87893-742-4 |editor-last=Purves |editor-first=Dale |edition=2nd |location=Sunderland, Mass |editor-last2=Williams |editor-first2=Stephen Mark}}</ref><ref name=":0">{{Cite book |title=Principles of neural science |date=2013 |publisher=McGraw-Hill medical |isbn=978-0-07-139011-8 |edition=5th |location=New York}}</ref> Later, it was found that chemicals could also be transported between cells through gap junctions.<ref>{{cite journal |pmid=5360587 |volume=166 |issue=3913 |title=Permeability and structure of junctional membranes at an electrotonic synapse |date=December 1969 |journal=Science |pages=1641–1643 |doi=10.1126/science.166.3913.1641 |last1=Payton |first1=B. W. |last2=Bennett |first2=M. V. L. |last3=Pappas |first3=G. D. |bibcode=1969Sci...166.1641P |s2cid=24701801}}</ref>

Implicit or explicit in most of the early studies is that the area of the gap junction was different in structure to the surrounding membranes in a way that made it look different. The gap junction had been shown to create a micro-environment between the two cells in the extracellular space or ''gap''. This portion of extracellular space was somewhat isolated from the surrounding space and also bridged by what we now call connexon pairs, which form even more tightly sealed bridges that cross the gap junction gap between two cells. When viewed in the plane of the membrane by freeze-fracture techniques, higher-resolution distribution of connexons within the gap junction plaque is possible.<ref>{{cite journal | pmid = 4935338 | doi=10.1083/jcb.47.1.49 | pmc=2108397 | volume=47 | issue=1 | title=An interpretation of liver cell membrane and junction structure based on observation of freeze-fracture replicas of both sides of the fracture |date=October 1970 | journal=J. Cell Biol. | pages=49–60 | last1 = Chalcroft | first1 = J. P. | last2 = Bullivant | first2 = S}}</ref>

Connexin free islands are observed in some junctions. The observation was largely without explanation until vesicles were shown by Peracchia using [[transmission electron microscopy]] (TEM) thin sections to be systematically associated with gap junction plaques.<ref>{{cite journal | pmid = 4120610 | pmc=2108965 | volume=57 | issue=1 | title=Low resistance junctions in crayfish. II. Structural details and further evidence for intercellular channels by freeze-fracture and negative staining |date=April 1973 | journal=J. Cell Biol. | pages=54–65 | last1 = Peracchia | first1 = C | doi = 10.1083/jcb.57.1.54}}</ref> Peracchia's study was probably also the first study to describe paired connexon structures, which he called a ''globule''. Studies showing vesicles associated with gap junctions and proposing the vesicle contents may move across the junction plaques between two cells were rare, as most studies focused on connexons rather than vesicles. A later study using a combination of microscopy techniques confirmed the early evidence of a probable function for gap junctions in intercellular vesicle transfer. Areas of vesicle transfer were associated with connexin free islands within gap junction plaques.<ref name ="Gruijters-vesicles"/> Connexin 43 has been shown to be necessary for the transfer of whole mitochondrias to neighboring cells, though whether the mitochondria is transferred directly through the membrane or within a vesicle has not been determined <ref>{{cite journal | last1 =Islam | first1 = M.| last2 = Das | first2 = S. |last3=Emin | first3=M. |display-authors= et al. | title=Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. | journal=Nat Med | volume=18 | pages=759–765 | year=2012 | issue = 5| doi=10.1038/nm.2736| pmid = 22504485| pmc = 3727429}}</ref>

===Electrical and chemical synapses===
Because of the widespread occurrence of gap junctions in cell types other than nerve cells, the term ''gap junction'' became more generally used than terms such as electrical synapse or nexus. Another dimension in the relationship between nerve cells and gap junctions was revealed by studying chemical synapse formation and gap junction presence. By tracing nerve development in leeches with gap junction expression suppressed it was shown that the bidirectional gap junction (electrical nerve synapse) needs to form between two cells before they can grow to form a unidirectional ''chemical nerve synapse''.<ref>{{cite journal |vauthors=Todd KL, Kristan WB, French KA |title=Gap junction expression is required for normal chemical synapse formation |journal=J. Neurosci. |volume=30 |issue=45 |pages=15277–85 |date=November 2010 |pmid=21068332 |pmc=3478946 |doi=10.1523/JNEUROSCI.2331-10.2010 }}</ref> The chemical nerve synapse is the synapse most often truncated to the more ambiguous term ''nerve synapse''.

===Composition===

====Connexins====
The purification<ref>{{Cite journal|doi=10.1083/jcb.54.3.646 |title=The isolation of mouse hepatocyte gap junctions: Preliminary Chemical Characterization and X-Ray Diffraction |year=1972 |last1=Goodenough |first1=D. A. |last2=Stoeckenius |first2=W. |journal=The Journal of Cell Biology |volume=54 |issue=3 |pages=646–56 |pmid=4339819 |pmc=2200277}}</ref><ref>{{Cite journal|doi=10.1083/jcb.61.2.557 |title=Bulk isolation of mouse hepatocyte gap junctions: Characterization of the Principal Protein, Connexin |year=1974 |last1=Goodenough |first1=D. A. |journal=The Journal of Cell Biology |volume=61 |pages=557–63 |pmid=4363961 |issue=2 |pmc=2109294}}</ref> of the intercellular gap junction plaques enriched in the channel forming protein ([[connexin]]) showed a protein forming hexagonal arrays in [[x-ray diffraction]]. Because of this, the systematic study and identification of the predominant [[gap junction protein]]<ref>{{Cite journal|doi=10.1083/jcb.103.3.767 |title=Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein |year=1986 |last1=Kumar |first1=N. M. |journal=The Journal of Cell Biology |volume=103 |pages=767–76 |pmid=2875078 |first2=NB |issue=3 |pmc=2114303 |last2=Gilula}}</ref> became possible. 
Refined ultrastructural studies by TEM<ref>{{cite journal |vauthors=McNutt NS, Weinstein RS |title=The ultrastructure of the nexus. A correlated thin-section and freeze-cleave study |journal=J. Cell Biol. |volume=47 |issue=3 |pages=666–88 |date=December 1970 |pmid=5531667 |pmc=2108148 |doi=10.1083/jcb.47.3.666}}</ref><ref>{{Cite journal|doi=10.1083/jcb.47.1.49 |title=An interpretation of liver cell membrane and junction structure based on observation of freeze-fracture replicas of both sides of the fracture |year=1970 |last1=Chalcroft |first1=J. P. |journal=The Journal of Cell Biology |volume=47 |pages=49–60 |pmid=4935338 |first2=S |issue=1 |pmc=2108397 |last2=Bullivant}}</ref> showed protein occurred in a complementary fashion in both cells participating in a gap junction plaque. The gap junction plaque is a relatively large area of membrane observed in TEM [[thin section]] and freeze fracture (FF) seen filled with transmembrane proteins in both tissues and more gently treated gap junction preparations. With the apparent ability for one protein alone to enable intercellular communication seen in gap junctions<ref>{{Cite journal|pmid=3815522 |year=1987 |author1=Young |first2=ZA |first3=NB |title=Functional assembly of gap junction conductance in lipid bilayers: demonstration that the major 27 kd protein forms the junctional channel |volume=48 |issue=5 |pages=733–43 |journal=Cell |doi=10.1016/0092-8674(87)90071-7 |last2=Cohn |last3=Gilula|s2cid=39342230 }}</ref> the term gap junction tended to become synonymous with a group of assembled connexins though this was not shown in vivo. Biochemical analysis of gap junction isolated from various tissues demonstrated a family of connexins.<ref>{{Cite journal |year=1985 |vauthors=Nicholson BJ, Gros DB, Kent SB, Hood LE, Revel JP |title=The Mr 28,000 gap junction proteins from rat heart and liver are different but related |volume=260 |issue=11 |pages=6514–6517 |journal=The Journal of Biological Chemistry |doi=10.1016/S0021-9258(18)88810-X |doi-access=free |pmid=2987225 }}</ref><ref>{{Cite journal |doi=10.1083/jcb.105.6.2621 |title=Connexin43: a protein from rat heart homologous to a gap junction protein from liver |year=1987 |vauthors=Beyer EC, Paul DL, Goodenough DA |journal=The Journal of Cell Biology |volume=105 |pages=2621–2629 |pmid=2826492 |issue=6 Pt 1 |pmc=2114703}}</ref><ref>{{Cite journal |pmid=3891760 |year=1985 |vauthors=Kistler J, Kirkland B, Bullivant S |title=Identification of a 70,000-D protein in lens membrane junctional domains |volume=101 |issue=1 |pages=28–35 |pmc=2113615 |journal=The Journal of Cell Biology |doi=10.1083/jcb.101.1.28}}</ref>

The ultrastructure and biochemistry of isolated gap junctions already referenced had indicated the connexins preferentially group in gap junction plaques or domains and connexins were the best characterized constituent. It has been noted that the organisation of proteins into arrays with a gap junction plaque may be significant.<ref name="ReferenceA"/><ref>{{cite journal|author1-link=Lucas Andrew Staehelin |vauthors=Staehelin LA |title=Three types of gap junctions interconnecting intestinal epithelial cells visualized by freeze-etching |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=69 |issue=5 |pages=1318–21 |date=May 1972 |pmid=4504340 |pmc=426690 |bibcode=1972PNAS...69.1318S |doi=10.1073/pnas.69.5.1318 |doi-access=free}}</ref> It is likely this early work was already reflecting the presence of more than just connexins in gap junctions. Combining the emerging fields of freeze-fracture to see inside membranes and [[immunocytochemistry]] to label cell components (Freeze-fracture replica immunolabelling or FRIL and thin section immunolabelling) showed gap junction plaques in vivo contained the connexin protein.<ref>{{Cite journal|pmid=3818793 |year=1987 |last1=Gruijters |first1=WTM |first2=J |first3=S |first4=DA |title=Immunolocalization of MP70 in lens fiber 16-17-nm intercellular junctions |volume=104 |issue=3 |pages=565–72 |pmc=2114558 |journal=The Journal of Cell Biology |doi=10.1083/jcb.104.3.565 |last2=Kistler |last3=Bullivant |last4=Goodenough}}</ref><ref name="Gruijters"/> Later studies using [[immunofluorescence]] microscopy of larger areas of tissue clarified diversity in earlier results. Gap junction plaques were confirmed to have variable composition being home to connexon and non-connexin proteins as well making the modern usage of the terms "gap junction" and "gap junction plaque" non-interchangeable.<ref name="Gruijters, WTM 1989 509–13">{{Cite journal|pmid=2691517 |journal=Journal of Cell Science |title=A non-connexon protein (MIP) is involved in eye lens gap-junction formation |volume=93 |issue=3 |pages=509–513 |last1=Gruijters |first1=WTM |year=1989|doi=10.1242/jcs.93.3.509 |url=http://jcs.biologists.org/cgi/content/abstract/93/3/509|url-access=subscription }}</ref> To summarize, in early literature the term "gap junction" referred to the regular gap between membranes in vertebrates and non-vertebrates apparently bridged by "globules". The junction correlated with the cell's ability to directly couple with its neighbors through pores in their membranes. Then for a while gap junctions were only referring to a structure that contains connexins and nothing more was thought to be involved. Later, the gap junction "plaque" was also found to contain other molecules that helped define it and make it function.

====The "plaque" or "formation plaque"====
[[File:Connexin43-Modulates-Cell-Polarity-and-Directional-Cell-Migration-by-Regulating-Microtubule-Dynamics-pone.0026379.s004.ogv|right|thumb|[[Immunofluorescence]] microscopy video of connexins being moved along [[microtubule]]s to the surface of a cell at 2.7 times normal speed.<ref name="ReferenceB"/>]]
Early descriptions of ''gap junctions'', ''connexons'' or ''innexons'' did not refer to them as such; many other terms were used. It is likely that ''synaptic disks''<ref>{{cite journal | pmid = 14069795 | pmc=2106854 | volume=19 | title=The occurrence of a subunit pattern in the unit membranes of club endings in mauthner cell synapses in goldfish brains |date=October 1963 | journal=J. Cell Biol. | pages=201–21 | doi = 10.1083/jcb.19.1.201 | last1 = Robertson | first1 = JD | issue = 1}}</ref> were an accurate reference to gap junction plaques. While the detailed structure and function of the connexon was described in a limited way at the time the gross ''disk'' structure was relatively large and easily seen by various TEM techniques. Disks allowed researchers using TEM to easily locate the connexons contained within the disk like patches in vivo and in vitro. The disk or ''plaque'' appeared to have structural properties different from those imparted by the connexons/innexons alone.<ref name=Hand72>{{cite journal | pmid = 4109925 | pmc=2108629 | volume=52 | issue=2 | title=The structural organization of the septate and gap junctions of Hydra |date=February 1972 | journal=J. Cell Biol. | pages=397–408 | doi = 10.1083/jcb.52.2.397 | last1 = Hand | first1 = AR | last2 = Gobel | first2 = S}}</ref> It was thought that if the area of membrane in the plaque transmitted signals, the area of membrane would have to be sealed in some way to prevent leakage.<ref>{{cite journal |vauthors=Loewenstein WR, Kanno Y |title=Studies on an epithelial (gland) cell junction. I. Modifications of surface membrane permeability |journal=J. Cell Biol. |volume=22 |pages=565–86 |date=September 1964 |pmid=14206423 |pmc=2106478 |doi=10.1083/jcb.22.3.565 |issue=3}}</ref>
Later studies showed gap junction plaques are home to non-connexin proteins, making the modern usage of the terms "gap junction" and "gap junction plaque" non-interchangeable as the area of the gap junction plaque may contain proteins other than connexins.<ref name="Gruijters, WTM 1989 509–13"/><ref name="Gruijters-vesicles"/> Just as connexins do not always occupy the entire area of the plaque, the other components described in the literature may be only long-term or short-term residents.<ref name=pmc3156236>{{cite journal |vauthors=Ozato-Sakurai N, Fujita A, Fujimoto T|title=The distribution of phosphatidylinositol 4,5-bisphosphate in acinar cells of rat pancreas revealed with the freeze-fracture replica labeling method |journal=PLOS ONE |volume=6 |issue=8 |article-number=e23567 |year=2011 |pmid=21858170 |pmc=3156236 |doi=10.1371/journal.pone.0023567 |editor1-last=Wong |editor1-first=Nai Sum|bibcode = 2011PLoSO...623567O |doi-access=free }}</ref><ref name="partners" /><ref>{{cite journal |last1=Strauss |first1=RE |last2=Gourdie |first2=RG |title=Cx43 and the Actin Cytoskeleton: Novel Roles and Implications for Cell-Cell Junction-Based Barrier Function Regulation |journal=Biomolecules |date=December 2020 |volume=10 |issue=12 |page=1656 |doi=10.3390/biom10121656 |pmid=33321985|pmc=7764618 |doi-access=free }}</ref>

Studies allowing views inside the plane of the membrane of gap junctions during formation indicated that a "formation plaque" formed between two cells prior to the connexins moving in. They were particle free areas—when observed by TEM FF, indicated very small or no [[transmembrane protein]]s were likely present. Little is known about what structures make up the formation plaque or how the formation plaque's structure changes when connexins and other components move in and out. One of the earlier studies of the formation of small gap junctions describes rows of particles and particle free halos.<ref>{{cite journal | pmid = 4135001 | pmc=2109180 | volume=62 | issue=1 | title=Assembly of gap junctions during amphibian neurulation |date=July 1974 | journal=J. Cell Biol. | pages=32–47 | doi = 10.1083/jcb.62.1.32 | last1 = Decker | first1 = RS | last2 = Friend | first2 = DS}}</ref> With larger gap junctions they were described as formation plaques with connexins moving into them. The particulate gap junctions were thought to form 4–6 hours after the formation plaques appeared.<ref>{{cite journal | pmid = 1083855 | pmc=2109697 | volume=69 | issue=3 | title=Hormonal regulation of gap junction differentiation |date=June 1976 | journal=J. Cell Biol. | pages=669–85 | doi = 10.1083/jcb.69.3.669 | last1 = Decker | first1 = RS}}</ref> How the connexins may be transported to the plaques using [[tubulin]] is becoming clearer.<ref name="ReferenceB"/><ref>{{cite journal |vauthors=Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM|title=Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=16 |pages=10446–51 |date=August 2002 |pmid=12149451 |pmc=124935 |doi=10.1073/pnas.162055899 |bibcode = 2002PNAS...9910446L |doi-access=free }}</ref>

The formation of plaque and the non-connexin part of the classical gap junction plaque have been difficult for early researchers to analyse. It appears in TEM FF and thin section to be a lipid membrane domain that can somehow form a comparatively rigid barrier to other lipids and proteins. There has been indirect evidence for certain lipids being preferentially involved with the formation plaque, however this cannot be considered definitive.<ref>{{cite journal | pmid = 1698798 | volume=96 | title=Increased gap junction assembly between cultured cells upon cholesterol supplementation |date=June 1990 | journal=J. Cell Sci. | pages=231–8 | issue=2 | last1 = Meyer | first1 = R | last2 = Malewicz | first2 = B | last3 = Baumann | first3 = WJ | last4 = Johnson | first4 = RG| doi=10.1242/jcs.96.2.231 }}</ref><ref>{{cite journal | pmid = 22049024 | doi=10.1091/mbc.E11-02-0141 | volume=23 | issue=1 | title=Gap junction assembly: roles for the formation plaque and regulation by the C-terminus of connexin43 | pmc=3248906 |date=January 2012 | journal=Mol. Biol. Cell | pages=71–86 | last1 = Johnson | first1 = R. G. | last2 = Reynhout | first2 = J. K. | last3 = Tenbroek | first3 = E. M. | last4 = Quade | first4 = B. J. | last5 = Yasumura | first5 = T. | last6 = Davidson | first6 = K. G. V. | last7 = Sheridan | first7 = J. D. | last8 = Rash | first8 = J. E.}}</ref> It is difficult to envisage breaking up the membrane to analyse membrane plaques without affecting their composition. By study of connexins still in membranes lipids associated with the connexins have been studied.<ref>{{cite journal | pmid = 19686581 | doi=10.1186/1741-7007-7-52 | volume=7 | title=Connexin channels and phospholipids: association and modulation | pmc=2733891 | year=2009 | journal=BMC Biol. | page=52 | last1 = Locke | first1 = Darren | last2 = Harris | first2 = Andrew L | issue=1 | doi-access=free }}</ref> It was found that specific connexins tended to associate preferentially with specific phospholipids. As formation plaques precede connexins these results still give no certainty as to what is unique about the composition of plaques themselves. Other findings show connexins associate with protein scaffolds used in another junction, the zonula occludens [[Tight junction protein 1|ZO-1]].<ref name="Naomi Kamasawa PMC">{{cite journal |vauthors=Li X, Kamasawa N, Ciolofan C, etal |title=Connexin45-containing neuronal gap junctions in rodent retina also contain connexin36 in both apposing hemiplaques, forming bihomotypic gap junctions, with scaffolding contributed by zonula occludens-1 |journal=J. Neurosci. |volume=28 |issue=39 |pages=9769–89 |date=September 2008 |pmid=18815262 |pmc=2638127 |doi=10.1523/JNEUROSCI.2137-08.2008}}</ref> While this helps us understand how connexins may be moved into a gap junction formation plaque, the composition of the plaque itself is still somewhat sketchy. Some headway on the in vivo composition of the gap junction plaque is being made using TEM FRIL.<ref name=pmc3156236/><ref name="Naomi Kamasawa PMC"/>

==See also==
* [[Gap junction modulation]]
* [[Gap junction protein]]
* [[Innexin]]
* [[Vinnexin]]
* [[Intercalated disc]]
* [[Ion channel]]
* [[Junctional complex]]
* [[Tight junction]]

==References==
{{Reflist|2}}

==Further reading==
*{{Cite book|editor1-first=Andrew |editor1-last=Harris |editor2-first=Darren |editor2-last=Locke |title=Connexins |publisher=Springer |year=2009 |location=New York |doi=10.1007/978-1-59745-489-6 |url=https://www.springer.com/978-1-934115-46-6 |isbn=978-1-934115-46-6}}

==External links==
{{Commons category|Gap junctions}}
* {{MeshName|Gap+Junctions}}

{{CellJunction}}
{{Ion channels}}
{{Signal transduction}}
{{Authority control}}

{{DEFAULTSORT:Gap Junction}}
[[Category:Cell communication]]
[[Category:Cell signaling]]
[[Category:Cell anatomy]]
[[Category:Articles containing video clips]]