View source for Connexin

{{Short description|Group of proteins which form the intermembrane channels of gap junctions}}
{{Infobox protein family
| Symbol = Connexin 
| Name = Connexin 
| image = 5er7.jpg
| width = 
| caption = Connexin-26 dodecamer. A gap junction, composed of twelve identical connexin proteins, six in the membrane of each cell. Each of these six units is a single polypeptide which passes the membrane four times (referred to as four-pass transmembrane proteins).
| Pfam= PF00029
| InterPro= IPR013092
| SMART= 
| Prosite = PDOC00341
| SCOP =     
| TCDB =  1.A.24
| OPM family= 194
| OPM protein= 2zw3
| PDB=    
}}

'''Connexins''' ('''Cx''') ([http://tcdb.org/search/result.php?tc=1.a.24 TC# 1.A.24]), or [[gap junction]] [[proteins]], are structurally related transmembrane proteins that assemble to form vertebrate gap junctions. An entirely different family of proteins, the [[innexins]], forms gap junctions in [[invertebrates]].<ref>{{cite book | vauthors = Lodish HF, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipursky SL, Darnell J | title = Molecular Cell Biology | edition = 5th | publisher = W.H. Freeman and Company | year = 2004 | location = New York | pages = 230–31 | url = https://archive.org/details/molecularcellbio00harv/page/230 | isbn = 0-7167-4366-3 | url-access = registration }}</ref> Each gap junction is composed of two hemichannels, or [[connexons]], which consist of homo- or heterohexameric arrays of connexins, and the connexon in one plasma membrane docks end-to-end with a connexon in the membrane of a closely opposed cell. The hemichannel is made of six connexin subunits, each of which consist of four transmembrane segments. Gap junctions are essential for many physiological processes, such as the coordinated depolarization of [[cardiac muscle]], proper embryonic development, and the conducted response in microvasculature. Connexins also have non-channel dependant functions relating to cytoskeleton and cell migration.<ref name="pmid22613178">{{cite journal | vauthors = Matsuuchi L, Naus CC | title = Gap junction proteins on the move: connexins, the cytoskeleton and migration | journal = Biochim Biophys Acta | volume = 1828 | issue = 1 | pages = 94–108 | date = January 2013 | pmid = 22613178 | doi = 10.1016/j.bbamem.2012.05.014 | doi-access = free }}</ref> For these reasons, mutations in connexin-encoding genes can lead to functional and developmental abnormalities.

==Nomenclature==
Connexins are commonly named according to their molecular weights, e.g. Cx26 is the connexin protein of 26 kDa. A competing nomenclature is the [[gap junction protein]] system, where connexins are sorted by their α (GJA) and β (GJB) forms, with additional connexins grouped into the C, D and E groupings, followed by an identifying number, e.g. [[GJA1]] corresponds to Cx43. Following a vote at the Gap Junction Conference (2007) in Elsinore the community agreed to use the GJ nomenclature system for the genes that encode connexins, but wished to retain the connexin nomenclature for the encoded proteins using the weight of the human protein for the numbering of orthologous proteins.

==Structure==
[[File:Connexon and connexin structure.svg|thumb|left|317x317px]]
Connexins contain four highly ordered [[Transmembrane domain|transmembrane segments]] (TMSs), primarily unstructured C and N cytoplasmic termini, a cytoplasmic loop (CL) and two extra-cellular loops, (EL-1) and (EL-2). Connexins are assembled in groups of six to form hemichannels, or connexons, and two hemichannels then combine to form a gap junction.

The crystal structure of the gap junction channel formed by human Cx26 (also known as GJB2) at 3.5 Å resolution is available.<ref name="pmid19340074">{{cite journal | vauthors = Maeda S, Nakagawa S, Suga M, Yamashita E, Oshima A, Fujiyoshi Y, Tsukihara T | title = Structure of the connexin 26 gap junction channel at 3.5 A resolution | journal = Nature | volume = 458 | issue = 7238 | pages = 597–602 | date = April 2009 | pmid = 19340074 | doi = 10.1038/nature07869 | bibcode = 2009Natur.458..597M | s2cid = 4431769 | issn = 1476-4687 }}</ref> The density map showed the two membrane-spanning hemichannels and the arrangement of the four TMSs of the six protomers forming each hemichannel. The hemichannels feature a positively charged cytoplasmic entrance, a funnel, a negatively charged transmembrane pathway, and an extracellular cavity. The pore is narrowed at the funnel, which is formed by the six amino-terminal helices lining the wall of the channel, which thus determines the molecular size restriction at the channel entrance.

The connexin gene family is diverse, with twenty-one identified members in the sequenced human genome, and twenty in the mouse (nineteen of which are orthologous pairs). They usually weigh between 25 and 60 kDa, and have an average length of 380 amino acids. The various connexins have been observed to combine into both homomeric and heteromeric gap junctions, each of which may exhibit different functional properties including pore conductance, size selectivity, charge selectivity, voltage gating, and chemical gating.<ref name="pmid16601118">{{cite journal | vauthors = Ayad WA, Locke D, Koreen IV, Harris AL | title = Heteromeric, but not homomeric, connexin channels are selectively permeable to inositol phosphates | journal = J. Biol. Chem. | volume = 281 | issue = 24 | pages = 16727–39 | date = June 2006 | pmid = 16601118 | doi = 10.1074/jbc.M600136200 |issn = 0021-9258| doi-access = free }}</ref>

==Biosynthesis and internalization==
A remarkable aspect of connexins is that they have a relatively short half-life of only a few hours.<ref name="Laird2006">{{cite journal | vauthors = Laird DW | title = Life cycle of connexins in health and disease | journal = Biochem. J. | volume = 394 | issue = Pt 3 | pages = 527–43 | date = March 2006 | pmid = 16492141 | pmc = 1383703 | doi = 10.1042/BJ20051922  }}</ref> The result is the presence of a dynamic cycle by which connexins are synthesized and replaced. It has been suggested that this short life span allows for more finely regulated physiological processes to take place, such as in the [[myometrium]].

===From the nucleus to the membrane===
As they are being translated by ribosomes, connexins are inserted into the membrane of the [[endoplasmic reticulum]] (ER).<ref name="pmid14980200">{{cite journal | vauthors = Bennett MV, Zukin RS | title = Electrical coupling and neuronal synchronization in the Mammalian brain | journal = Neuron | volume = 41 | issue = 4 | pages = 495–511 | date = February 2004 | pmid = 14980200 | doi = 10.1016/s0896-6273(04)00043-1 | s2cid = 18566176 | doi-access = free }}</ref> It is in the ER that connexins are properly folded, yielding two extracellular loops, EL-1 and EL-2. It is also in the ER that the [[oligomerization]] of connexin molecules into hemichannels begins, a process which may continue in the UR-Golgi intermediate compartment as well.<ref name="Laird2006" /> The arrangements of these hemichannels can be homotypic, heterotypic, and combined heterotypic/heteromeric. After exiting the [[Endoplasmic reticulum|ER]] and passing through the [[Vesicular-tubular cluster|ERGIC]], the folded connexins will usually enter the ''cis''-Golgi network.<ref name="pmid7691412">{{cite journal | vauthors = Musil LS, Goodenough DA | title = Multisubunit assembly of an integral plasma membrane channel protein, gap junction connexin43, occurs after exit from the ER | journal = Cell | volume = 74 | issue = 6 | pages = 1065–77 | date = September 1993 | pmid = 7691412 | doi = 10.1016/0092-8674(93)90728-9 | s2cid = 12169415 }}</ref> However, some connexins, such as Cx26 may be transported independent of the Golgi.<ref name="pmid10207897">{{cite book | vauthors = Evans WH, Ahmad S, Diez J, George CH, Kendall JM, Martin PE | title = Novartis Foundation Symposium 219 - Gap Junction-Mediated Intercellular Signalling in Health and Disease | chapter = Trafficking pathways leading to the formation of gap junctions | volume = 219 | pages = 44–54; discussion 54–9 | date = 1999 | pmid = 10207897 | doi = 10.1002/9780470515587.ch4 | series = Novartis Foundation Symposia | isbn = 9780470515587 }}</ref><ref name="pmid10085106">{{cite journal | vauthors = George CH, Kendall JM, Evans WH | title = Intracellular trafficking pathways in the assembly of connexins into gap junctions | journal = J. Biol. Chem. | volume = 274 | issue = 13 | pages = 8678–85 | date = March 1999 | pmid = 10085106 | doi = 10.1074/jbc.274.13.8678| doi-access = free }}</ref><ref name="pmid9792698">{{cite journal | vauthors = George CH, Kendall JM, Campbell AK, Evans WH | title = Connexin-aequorin chimerae report cytoplasmic calcium environments along trafficking pathways leading to gap junction biogenesis in living COS-7 cells | journal = J. Biol. Chem. | volume = 273 | issue = 45 | pages = 29822–9 | date = November 1998 | pmid = 9792698 | doi = 10.1074/jbc.273.45.29822| doi-access = free }}</ref><ref name="pmid9430718">{{cite journal | vauthors = Martin PE, George CH, Castro C, Kendall JM, Capel J, Campbell AK, Revilla A, Barrio LC, Evans WH | title = Assembly of chimeric connexin-aequorin proteins into functional gap junction channels. Reporting intracellular and plasma membrane calcium environments | journal = J. Biol. Chem. | volume = 273 | issue = 3 | pages = 1719–26 | date = January 1998 | pmid = 9430718 | doi = 10.1074/jbc.273.3.1719| doi-access = free }}</ref><ref name="pmid12064596">{{cite journal | vauthors = Martin PE, Errington RJ, Evans WH | title = Gap junction assembly: multiple connexin fluorophores identify complex trafficking pathways | journal = Cell Commun. Adhes. | volume = 8 | issue = 4–6 | pages = 243–8 | date = 2001 | pmid = 12064596 | doi = 10.3109/15419060109080731| s2cid = 3029281 | doi-access = free }}</ref>

===Gap junction assembly===
After being inserted into the plasma membrane of the cell, the hemichannels freely diffuse within the lipid bilayer.<ref name="pmid16159960">{{cite journal | vauthors = Thomas T, Jordan K, Simek J, Shao Q, Jedeszko C, Walton P, Laird DW | title = Mechanisms of Cx43 and Cx26 transport to the plasma membrane and gap junction regeneration | journal = J. Cell Sci. | volume = 118 | issue = Pt 19 | pages = 4451–62 | date = October 2005 | pmid = 16159960 | doi = 10.1242/jcs.02569 | s2cid = 13486416 | doi-access =  }}</ref> Through the aid of specific proteins, mainly [[cadherins]], the hemichannels are able to dock with hemichannels of adjacent cells forming gap junctions.<ref name="pmid1650371">{{cite journal | vauthors = Jongen WM, Fitzgerald DJ, Asamoto M, Piccoli C, Slaga TJ, Gros D, Takeichi M, Yamasaki H | title = Regulation of connexin 43-mediated gap junctional intercellular communication by Ca2+ in mouse epidermal cells is controlled by E-cadherin | journal = J. Cell Biol. | volume = 114 | issue = 3 | pages = 545–55 | date = August 1991 | pmid = 1650371 | pmc = 2289094 | doi = 10.1083/jcb.114.3.545}}</ref> Recent studies have shown the existence of communication between adherens junctions and gap junctions,<ref name="pmid15741167">{{cite journal | vauthors = Wei CJ, Francis R, Xu X, Lo CW | title = Connexin43 associated with an N-cadherin-containing multiprotein complex is required for gap junction formation in NIH3T3 cells | journal = J. Biol. Chem. | volume = 280 | issue = 20 | pages = 19925–36 | date = May 2005 | pmid = 15741167 | doi = 10.1074/jbc.M412921200 | s2cid = 770387 | url = http://www.columbia.edu/cu/biology/dept/seminarPDFfiles/Weietal,%20Lo.pdf | doi-access = free }}</ref> suggesting a higher level of coordination than previously thought.
[[File:Life cycle and protein associations of connexins.jpg|thumb|center|600px| Life cycle and protein associations of connexins. Connexins are synthesized on ER-bound ribosomes and inserted into the ER cotranslationally. This is followed by oligomerization between the ER and trans-Golgi network (depending on the connexin type) into connexons, which are then delivered to the membrane via the actin or microtubule networks. Connexons may also be delivered to the plasma membrane by direct transfer from the rough ER. Upon insertion into the membrane, connexons may remain as hemichannels or they dock with compatible connexons on adjacent cells to form gap junctions. Newly delivered connexons are added to the periphery of pre-formed gap junctions, while the central "older" gap junction fragment are degraded by internalization of a double-membrane structure called an annular junction into one of the two cells, where subsequent lysosomal or proteasomal degradation occurs, or in some cases the connexons are recycled to the membrane (indicated by dashed arrow). During their life cycle, connexins associate with different proteins, including (1) cytoskeletal components as microtubules, actin, and actin-binding proteins α-[[spectrin]] and [[DBN1|drebrin]], (2) junctional molecules including adherens junction components such as cadherins, [[Alpha-catenin|α-catenin]], and [[Beta catenin|β-catenin]], as well as tight junction components such as [[Tight junction protein 1|ZO-1]] and [[Tight junction protein 2|ZO-2]], (3) enzymes such as kinases and phosphatases which regulate the assembly, function, and degradation, and (4) other proteins such as caveolin. This image was prepared by Hanaa Hariri for Dbouk et al., 2009.<ref name="Dbouk09">{{cite journal | vauthors = Dbouk HA, Mroue RM, El-Sabban ME, Talhouk RS | title = Connexins: a myriad of functions extending beyond assembly of gap junction channels | journal = Cell Commun Signal | volume = 7 | pages = 4 | date = March 2009 | pmid = 19284610 | pmc = 2660342 | doi = 10.1186/1478-811X-7-4 | doi-access = free }}</ref>]]

==Function==
Connexin gap junctions are found only in [[vertebrate]]s, while a functionally analogous (but genetically unrelated) group of proteins, the [[innexin]]s, are responsible for gap junctions in [[invertebrate]] species. [[Innexin]] orthologs have also been identified in [[Chordate]]s, but they are no longer capable of forming gap junctions. Instead, the channels formed by these proteins (called [[pannexin]]s) act as very large transmembrane pores that connect the intra- and extracellular compartments.

Within the [[Central nervous system|CNS]], gap junctions provide electrical coupling between progenitor cells, neurons, and glial cells. By using specific connexin [[Knockout mouse|knockout mice]], studies revealed that cell coupling is essential for visual signaling. In the [[retina]], ambient light levels influence cell coupling provided by gap junction channels, adapting the visual function for various lighting conditions. Cell coupling is governed by several mechanisms, including connexin expression.<ref name="Kihara">{{cite journal |vauthors=Kihara AH, de Castro LM, Moriscot AS, Hamassaki DE | title = Prolonged dark adaptation changes connexin expression in the mouse retina | journal = J Neurosci Res | volume = 83 | issue = 7 | pages = 1331–41 |date=May 2006 | pmid = 16496335  | doi = 10.1002/jnr.20815| s2cid = 2919282 }}</ref>

Decrock et al.''.'' have discussed a multilevel platform via which connexins and pannexins can influence the following cellular functions within a tissue: (1) connexin gap junctional channels (GJCs) enable direct cell-cell communication of small molecules, (2) connexin hemichannels and pannexin channels can contribute to [[Autocrine signalling|autocrine]]/[[Paracrine signalling|paracrine signaling]] pathways, and (3) different structural domains of these proteins allow for channel-independent functions, such as [[Cell adhesion|cell-cell adhesion]], interactions with the [[cytoskeleton]], and the activation of intracellular signaling pathways.<ref name="pmid26118660">{{cite journal | vauthors = Decrock E, De Bock M, Wang N, Bultynck G, Giaume C, Naus CC, Green CR, Leybaert L | title = Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology? | journal = Cell. Mol. Life Sci. | volume = 72 | issue = 15 | pages = 2823–51 | date = August 2015 | pmid = 26118660 | doi = 10.1007/s00018-015-1962-7 | s2cid = 17170098 |issn = 1420-9071 | pmc = 11113968 }}</ref> Thus, connexins and pannexins have multifaceted contributions to brain development and specific processes in the neuro-glio-vascular unit, including synaptic transmission and plasticity, glial signaling, vasomotor control, cell movement, and blood-brain barrier integrity in the mature CNS.<ref name="pmid26118660"/><ref name="pmid22613178"/>

===Substrate specificity===
Different connexins may exhibit differing specificities for solutes. For example, [[adenosine]] passed about 12-fold better through channels formed by Cx32 while [[Adenosine monophosphate|AMP]] and [[Adenosine diphosphate|ADP]] passed about 8-fold better, and [[Adenosine triphosphate|ATP]] greater than 300-fold better, through channels formed by Cx43. Thus, addition of phosphate to adenosine appears to shift its relative permeability from channels formed by Cx32 to channels formed by Cx43. This may have functional consequence because the energy status of a cell could be controlled via connexin expression and channel formation.<ref name="pmid12119284">{{cite journal | vauthors = Goldberg GS, Moreno AP, Lampe PD | title = Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP | journal = J. Biol. Chem. | volume = 277 | issue = 39 | pages = 36725–30 | date = September 2002 | pmid = 12119284 | doi = 10.1074/jbc.M109797200 | issn = 0021-9258 | doi-access = free }}</ref>

===Transport reaction===
The transport reaction catalyzed by connexin gap junctions is:
:Small molecules (cell 1 cytoplasm) ⇌ small molecules (cell 2 cytoplasm)

==Human connexins and clinical significance==
{| class="sortable wikitable"
! '''Connexin'''
! '''Gene'''
! '''Location and Function'''
|- 
|Cx43
|[[GJA1]]
|Expressed at the surface of vasculature with atherosclerotic plaque, and up-regulated during atherosclerosis in mice. May have pathological effects. Also expressed between [[granulosa cells]], which is required for proliferation. Normally expressed in astrocytes, also detected in most of the human astrocytomas and in the astroglial component of glioneuronal tumors.<ref name="pmid11484816"/> It is also the main cardiac connexin, found mainly in ventricular myocardium.<ref name="pmid9130448">{{cite journal | vauthors = Verheule S, van Kempen MJ, te Welscher PH, Kwak BR, Jongsma HJ | title = Characterization of gap junction channels in adult rabbit atrial and ventricular myocardium | journal = Circ. Res. | volume = 80 | issue = 5 | pages = 673–81 | date = May 1997 | pmid = 9130448 | doi = 10.1161/01.res.80.5.673 }}</ref> Associated with [[oculodentodigital dysplasia]].
|-
|Cx46 
|[[GJA3]]
|
|-
|Cx37 
|[[GJA4]]
|Induced in vascular smooth muscle during coronary arteriogenesis. Cx37 mutations are not lethal. Forms gap junctions between oocytes and granulosa cells, and are required for oocyte survival.
|-
|Cx40 
|[[GJA5]]
|Expressed selectively in atrial myocytes. Responsible for mediating the coordinated electrical activation of atria.<ref name="pmid16790700">{{cite journal | vauthors = Gollob MH, Jones DL, Krahn AD, Danis L, Gong XQ, Shao Q, Liu X, Veinot JP, Tang AS, Stewart AF, Tesson F, Klein GJ, Yee R, Skanes AC, Guiraudon GM, Ebihara L, Bai D|display-authors = 6 | title = Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation | journal = N. Engl. J. Med. | volume = 354 | issue = 25 | pages = 2677–88 | date = June 2006 | pmid = 16790700 | doi = 10.1056/NEJMoa052800 | doi-access = free }}</ref>
|-
|Cx33
|[[GJA6]]<BR>(GJA6P)
|[[Pseudogene]] in humans
|-
|Cx50 
|[[GJA8]]
|Gap junctions between A-typ horizontal cells in mouse and rabbit retina<ref>{{cite book | author = Massey, Stephen| title = Connexins: A Guide| pages = 3–?|  edition= 1st | publisher = Springer-Verlag Gmbh | date=16 January 2009 | isbn = 978-1-934115-46-6}}</ref>
|-
|Cx59 
|[[GJA10]]
|
|- 
|Cx62 
|[[GJA10]]
|Human Cx62 complies Cx57 (mouse). Location in axon-bearing B-typ horizontal cell in rabbit retina<ref>{{cite book |author1=Beyer, Eric C. |author2=Berthound, Viviana M. | title = Connexins: A Guide| pages = 387–417| edition= 1st | publisher = Springer-Verlag Gmbh | date=16 January 2009 | isbn = 978-1-934115-46-6}}</ref>
|-
|Cx32 
|[[GJB1]]
|Major component of the peripheral myelin. Mutations in the human gene cause X-linked [[Charcot-Marie-Tooth|Charcot-Marie-Tooth disease]], a hereditary neuropathy. In human normal brain CX32 expressed in neurons and oligodendrocytes.<ref name="pmid11484816">{{cite journal | vauthors = Aronica E, Gorter JA, Jansen GH, Leenstra S, Yankaya B, Troost D | title = Expression of connexin 43 and connexin 32 gap-junction proteins in epilepsy-associated brain tumors and in the perilesional epileptic cortex | journal = Acta Neuropathol. | volume = 101 | issue = 5 | pages = 449–59 | date = May 2001 | pmid = 11484816 | doi = 10.1007/s004010000305 | s2cid = 6738913 }}</ref>
|- 
|Cx26 
|[[GJB2]]
| Mutated in [[Vohwinkel syndrome]]<ref name="pmid23675785">{{cite journal | vauthors = Avshalumova L, Fabrikant J, Koriakos A | title = Overview of skin diseases linked to connexin gene mutations | journal = Int J Dermatol | volume = 53 | issue = 2 | pages = 192–205 | date = February 2014 | pmid = 23675785 | doi = 10.1111/ijd.12062 | s2cid = 205187359 }}</ref> as well as [[Keratitis–ichthyosis–deafness syndrome|Keratitis-Icthyosis-Deafness (KID) Syndrome]].<ref name="pmid23675785"/>
|-
|Cx31 
|[[GJB3]]
|Can be associated with [[Erythrokeratodermia variabilis]].
|-
|Cx30.3 
|[[GJB4]]
|Fonseca ''et al.'' confirmed Cx30.3 expression in [[thymocyte]]s.<ref name="pmid15234537">{{cite journal | vauthors = Fonseca PC, Nihei OK, Urban-Maldonado M, Abreu S, de Carvalho AC, Spray DC, Savino W, Alves LA | title = Characterization of connexin 30.3 and 43 in thymocytes | journal = Immunol. Lett. | volume = 94 | issue = 1–2 | pages = 65–75 | date = June 2004 | pmid = 15234537 | doi = 10.1016/j.imlet.2004.03.019 }}</ref> Can be associated with Erythrokeratodermia variabilis.
|-
|Cx31.1 
|[[GJB5]]
|
|-
|Cx30 
|[[GJB6]]
| Mutated in [[Clouston syndrome]] (hidrotic ectodermal dysplasia)<ref name="pmid23675785"/>
|-
|Cx25 
|[[GJB7]]
|
|- 
|Cx45 
|[[GJC1]]/GJA7
|Human pancreatic ductal epithelial cells.<ref name="pmid12499933">{{cite journal | vauthors = Tai MH, Olson LK, Madhukar BV, Linning KD, Van Camp L, Tsao MS, Trosko JE | title = Characterization of gap junctional intercellular communication in immortalized human pancreatic ductal epithelial cells with stem cell characteristics | journal = Pancreas | volume = 26 | issue = 1 | pages = e18–26 | date = January 2003 | pmid = 12499933 | doi = 10.1097/00006676-200301000-00025 | s2cid = 34571252 }}</ref> Atrio-ventricular node.
|-
|Cx47 
|[[GJC2]]/GJA12
|Expressed in oligodendrocyte gap junctions<ref name="pmid16203097">{{cite journal | vauthors = Kamasawa N, Sik A, Morita M, Yasumura T, Davidson KG, Nagy JI, Rash JE | title = Connexin-47 and connexin-32 in gap junctions of oligodendrocyte somata, myelin sheaths, paranodal loops and Schmidt-Lanterman incisures: implications for ionic homeostasis and potassium siphoning | journal = Neuroscience | volume = 136 | issue = 1 | pages = 65–86 | date = 2005 | pmid = 16203097 | pmc = 1550704 | doi = 10.1016/j.neuroscience.2005.08.027 }}</ref>
|-
|Cx31.3  
|[[GJC3]]
|Human ortholog of murine Cx29. Not known to form gap junctions.<ref name="pmid18353664">{{cite journal | vauthors = Sargiannidou I, Ahn M, Enriquez AD, Peinado A, Reynolds R, Abrams C, Scherer SS, Kleopa KA | title = Human oligodendrocytes express Cx31.3: function and interactions with Cx32 mutants | journal = Neurobiol. Dis. | volume = 30 | issue = 2 | pages = 221–33 | date = May 2008 | pmid = 18353664 | pmc = 2704064 | doi = 10.1016/j.nbd.2008.01.009  }}</ref>
|-
|Cx36 
|[[GJD2]]/GJA9
|Pancreatic beta cell function, mediating the release of insulin. [[Neurons]] throughout the [[Central Nervous System|central nervous system]] where they synchronize neural activity.<ref name="pmid15217338">{{cite journal | vauthors = Connors BW, Long MA | title = Electrical synapses in the mammalian brain | journal = Annu. Rev. Neurosci. | volume = 27 | pages = 393–418 | date = 2004 | pmid = 15217338 | doi = 10.1146/annurev.neuro.26.041002.131128 | url = https://zenodo.org/record/894386 }}</ref>
|-
|Cx31.9 
|[[GJD3]]/GJC1
|
|- 
|Cx39
|[[GJD4]]
|
|- 
|Cx40.1 
|[[GJD4]]
|
|-
|Cx23 
|[[GJE1]]
|}
Gap junctions are essential for many physiological processes, such as the coordinated depolarization of [[cardiac muscle]], proper embryonic development, and the conducted response in microvasculature. For this reason, deletion or mutation of the various connexin [[Protein isoform|isoforms]] produces distinctive phenotypes and pathologies.<ref name="pmid20840374">{{cite journal | vauthors = Pfenniger A, Wohlwend A, Kwak BR | title = Mutations in connexin genes and disease | journal = Eur. J. Clin. Invest. | volume = 41 | issue = 1 | pages = 103–16 | date = January 2011 | pmid = 20840374 | doi = 10.1111/j.1365-2362.2010.02378.x | s2cid = 24404442 | issn = 1365-2362| doi-access = free }}</ref> While mutations in Cx43 are mostly linked to oculodentodigital dysplasia, Cx47 mutations are associated with [[Pelizaeus–Merzbacher disease|Pelizaeus-Merzbacher]]-like disease and lymphedema. Cx40 mutations are principally linked to atrial fibrillation. Mutations in Cx37 have not yet been described, but polymorphisms in the Cx37 gene have been implicated in the development of arterial disease.<ref name="pmid36067749">{{cite journal | vauthors = Fang JS, Burt JM | title = Connexin37 Regulates Cell Cycle in the Vasculature | journal = J Vasc Res | volume = 60| issue = 2| pages = 73–86 | date = September 2022 | pmid = 36067749 | doi = 10.1159/000525619 | doi-access = free }}</ref><ref name="pmid24966059">{{cite journal | vauthors = Molica F, Meens MJ, Morel S, Kwak BR | title = Mutations in cardiovascular connexin genes | journal = Biology of the Cell | volume = 106 | issue = 9 | pages = 269–93 | date = September 2014 | pmid = 24966059 | doi = 10.1111/boc.201400038 | s2cid = 10070999 }}</ref>

== References ==
{{Reflist}}

== Sources ==
* {{CCBYSASource|sourcepath= http://tcdb.org/search/result.php?tc=1.a.24|sourcearticle= 1.A.24 The Gap Junction-forming Connexin (Connexin) Family |revision=699838558}}

==External links==
* {{commons-inline|Category:Connexins|connexins}}
* {{MeshName|Connexins}}

{{Ion channels}}
{{Epithelial proteins}}

{{Authority control}}

[[Category:Protein families]]
[[Category:Membrane channels]]
[[Category:Membrane proteins]]
[[Category:Transmembrane proteins]]
[[Category:Transmembrane transporters]]
[[Category:Transport proteins]]
[[Category:Integral membrane proteins]]