Editing Gap junction (section)

==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=9780470513408 }}</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 |pages=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 |pages=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 |pages=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 invertibrates, gap gunctions 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 }}</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
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  |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
  |pages=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 |pages=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 [[sdenosine 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.