View source for GJA1

{{short description|Protein-coding gene in humans}}
{{cs1 config|name-list-style=vanc}}
{{Infobox_gene}}
{{Infobox protein family
| Symbol = Connexin43
| Name = Connexin43
| image = PDB 1r5s EBI.jpg
| width =
| caption = connexin 43 carboxyl terminal domain
| Pfam = PF03508
| Pfam_clan =
| InterPro = IPR013124
| SMART =
| PROSITE =
| MEROPS =
| SCOP =
| TCDB = 1.A.24
| OPM family =
| OPM protein =
| CAZy =
| CDD =
}}
'''Gap junction alpha-1 protein''' ('''GJA1'''), also known as '''connexin 43''' ('''Cx43'''), is a [[protein]] that in humans is encoded by the ''GJA1'' [[gene]] on chromosome 6.<ref name="pmid10331943">{{cite journal | vauthors = Boyadjiev SA, Jabs EW, LaBuda M, Jamal JE, Torbergsen T, Ptácek LJ, Rogers RC, Nyberg-Hansen R, Opjordsmoen S, Zeller CB, Stine OC, Stalker HJ, Zori RT, Shapiro RE | title = Linkage analysis narrows the critical region for oculodentodigital dysplasia to chromosome 6q22-q23 | journal = Genomics | volume = 58 | issue = 1 | pages = 34–40 | date = May 1999 | pmid = 10331943 | doi = 10.1006/geno.1999.5814 }}</ref><ref name="pmid1646158">{{cite journal | vauthors = Fishman GI, Eddy RL, Shows TB, Rosenthal L, Leinwand LA | title = The human connexin gene family of gap junction proteins: distinct chromosomal locations but similar structures | journal = Genomics | volume = 10 | issue = 1 | pages = 250–256 | date = May 1991 | pmid = 1646158 | doi = 10.1016/0888-7543(91)90507-B }}</ref><ref name = "entrez">{{cite web | title = Entrez Gene: GJA1 gap junction protein, alpha 1, 43kDa| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2697}}</ref> As a [[connexin]], GJA1 is a component of [[gap junction]]s, which allow for gap junction [[intercellular communication]] (GJIC) between [[Cell (biology)|cell]]s to regulate [[cell death]], [[Cell proliferation|proliferation]], and [[Cellular differentiation|differentiation]].<ref name = "pmid25560303">{{cite journal | vauthors = Cheng JC, Chang HM, Fang L, Sun YP, Leung PC | title = TGF-β1 up-regulates connexin43 expression: a potential mechanism for human trophoblast cell differentiation | journal = Journal of Cellular Physiology | volume = 230 | issue = 7 | pages = 1558–1566 | date = Jul 2015 | pmid = 25560303 | doi = 10.1002/jcp.24902 | s2cid = 28968035 }}</ref> As a result of its function, GJA1 is implicated in many biological processes, including [[muscle contraction]], [[embryo]]nic development, [[inflammation]], and [[spermatogenesis]], as well as [[disease]]s, including [[oculodentodigital dysplasia]] (ODDD), heart malformations, and [[cancer]]s.<ref name = "entrez"/><ref name = "pmid22918484">{{cite journal | vauthors = Chevallier D, Carette D, Segretain D, Gilleron J, Pointis G | title = Connexin 43 a check-point component of cell proliferation implicated in a wide range of human testis diseases | journal = Cellular and Molecular Life Sciences | volume = 70 | issue = 7 | pages = 1207–1220 | date = Apr 2013 | pmid = 22918484 | doi = 10.1007/s00018-012-1121-3 | s2cid = 11855947 | pmc = 11113700 }}</ref><ref name = "pmid25110696">{{cite journal | vauthors = Vliagoftis H, Ebeling C, Ilarraza R, Mahmudi-Azer S, Abel M, Adamko D, Befus AD, Moqbel R | title = Connexin 43 expression on peripheral blood eosinophils: role of gap junctions in transendothelial migration | journal = BioMed Research International | volume = 2014 | pages = 803257 | date = 2014 | pmid = 25110696 | doi = 10.1155/2014/803257 | pmc=4109672| doi-access = free }}</ref>
==Structure==
GJA1 is a 43.0 kDa [[protein]] composed of 382 [[amino acids]].<ref>{{cite web|title=Protein sequence of human GJA1 (Uniprot ID: P17302)|url=http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P17302|website=Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)|access-date=18 September 2015|archive-url=https://web.archive.org/web/20151005143620/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P17302|archive-date=5 October 2015|url-status=dead}}</ref> GJA1 contains a long [[C-terminal]] tail, an [[N-terminal]] domain, and multiple [[transmembrane]] domains. The protein passes through the [[phospholipid bilayer]] four times, leaving its C- and N-terminals exposed to the [[cytoplasm]].<ref name = "pmid24434540">{{cite journal | vauthors = Laird DW | title = Syndromic and non-syndromic disease-linked Cx43 mutations | journal = FEBS Letters | volume = 588 | issue = 8 | pages = 1339–1348 | date = Apr 2014 | pmid = 24434540 | doi = 10.1016/j.febslet.2013.12.022 | s2cid = 20651016 | doi-access = free }}</ref> The C-terminal tail is composed of 50 [[amino acid]]s and includes [[post-translational modification]] sites, as well as binding sites for [[transcription factor]]s, [[cytoskeleton]] elements, and other proteins.<ref name = "pmid24434540"/><ref name = "pmid22155212">{{cite journal | vauthors = Kameritsch P, Pogoda K, Pohl U | title = Channel-independent influence of connexin 43 on cell migration | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1818 | issue = 8 | pages = 1993–2001 | date = Aug 2012 | pmid = 22155212 | doi = 10.1016/j.bbamem.2011.11.016 | doi-access = free }}</ref> As a result, the C-terminal tail is central to functions such as regulating pH gating and channel assembly. Notably, the DNA region of the ''GJA1'' gene encoding this tail is highly conserved, indicating that it is either resistant to mutations or becomes lethal when mutated. Meanwhile, the N-terminal domain is involved in channel gating and oligomerization and, thus, may control the switch between the channel's open and closed states. The transmembrane domains form the gap junction channel while the [[extracellular]] loops facilitate proper channel docking. Moreover, two extracellular loops form disulfide bonds that interact with two hexamers to form a complete gap junction channel.<ref name = "pmid24434540"/>
The '''connexin-43 internal ribosome entry site''' is an [[Cis-regulatory element|RNA element]] present in the [[Five prime untranslated region|5' UTR]] of the [[mRNA]] of GJA1. This [[internal ribosome entry site]] (IRES) allows cap independent [[translation (biology)|translation]] during conditions such as [[heat shock]] and stress.<ref>{{cite journal | vauthors = Schiavi A, Hudder A, Werner R | title = Connexin43 mRNA contains a functional internal ribosome entry site | journal = FEBS Letters | volume = 464 | issue = 3 | pages = 118–122 | date = Dec 1999 | pmid = 10618489 | doi = 10.1016/S0014-5793(99)01699-3 | s2cid = 26020820 | doi-access = free }}</ref>
{{Infobox rfam
| Name = Connexin-43 internal ribosome entry site (IRES)
| image = RF00487.jpg
| width =
| caption = Predicted [[secondary structure]] and [[sequence conservation]] of IRES_Cx43
| Symbol = IRES_Cx43
| AltSymbols =
| Rfam = RF00487
| miRBase =
| miRBase_family =
| RNA_type = [[Cis-regulatory element|Cis-reg]]; [[Internal ribosome entry site|IRES]]
| Tax_domain = [[Eukaryota]]
| GO = {{GO|0043022}}
| SO = {{SO|0000243}}
| CAS_number =
| EntrezGene =
| HGNCid =
| OMIM =
| PDB =
| RefSeq =
| Chromosome =
| Arm =
| Band =
| LocusSupplementaryData =
}}
== Function ==
[[File:Microphotograph of connexin 43 distribution in the rat myocardium.jpg|thumb|Connexin 43 distribution in the rat myocardium (gap junctions between cardiomyocytes)]]
As a member of the [[connexin]] family, GJA1 is a component of [[gap junction]]s, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as small [[ions]] and [[secondary messenger]]s, to maintain [[homeostasis]].<ref name="entrez"/><ref name = "pmid24434540"/><ref name = "pmid25843295">{{cite journal | vauthors = Ghosh S, Kumar A, Chandna S | title = Connexin-43 downregulation in G2/M phase enriched tumour cells causes extensive low-dose hyper-radiosensitivity (HRS) associated with mitochondrial apoptotic events | journal = Cancer Letters | volume = 363 | issue = 1 | pages = 46–59 | date = Jul 2015 | pmid = 25843295 | doi = 10.1016/j.canlet.2015.03.046 }}</ref>
GJA1 is the most ubiquitously expressed connexin and is detected in most cell types.<ref name = "entrez"/><ref name = "pmid22918484"/><ref name = "pmid24434540"/>
It is the major protein in [[heart]] gap junctions and is purported to play a crucial role in the synchronized contraction of the heart.<ref name = "entrez"/> Despite its key role in the heart and other vital organs, GJA1 has a short [[half-life]] (only two to four hours), indicating that the protein undergoes daily [[Cell turnover|turnover]] in the heart and may be highly abundant or compensated with other connexins.<ref name = "pmid24434540"/>
GJA1 is also largely involved in [[embryo]]nic development.<ref name = "entrez"/><ref name = "pmid25560303"/> For instance, [[transforming growth factor-beta]] 1 (TGF-β1) was observed to induce GJA1 expression via the [[SMAD (protein)|Smad]] and [[Extracellular signal-regulated kinases|ERK1]]/2 [[signaling pathway]]s, resulting in [[trophoblast]] cell differentiation into the [[placenta]].<ref name = "pmid25560303"/>
Furthermore, GJA1 is expressed in many [[immune cells]], such as [[eosinophil]]s and [[T cell]]s, where its gap junction function promotes the maturation and activation of these cells and, by extension, the cross-communication necessary to mount an [[inflammation|inflammatory]] response.<ref name = "pmid25110696"/> It has also been shown that [[Uterus|uterine]] [[macrophage]] directly physically couple with uterine [[Muscle cell|myocytes]] through GJA1, transferring [[Ca²⁺]], to promote uterine muscle contraction and excitation during human [[Childbirth|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>
In addition, GJA1 can be found in the [[Leydig cell]]s and [[seminiferous tubules]] between [[Sertoli cell]]s and [[spermatogonia]] or [[primary spermatocyte]]s, where it plays a key role in [[spermatogenesis]] and [[testis]] development through controlling the [[tight junction]] proteins in the [[blood-testis barrier]].
While it is a channel protein, GJA1 can also perform channel-independent functions. In the [[cytoplasm]], the protein regulates the [[microtubule]] network and, by extension, [[cell migration]] and [[Cell polarity|polarity]].<ref name = "pmid22918484"/><ref name = "pmid22155212"/> This function has been observed in [[brain]] and heart development, as well as wound-healing in [[endothelial]] cells.<ref name = "pmid22155212"/> GJA1 has also been observed to localize to the mitochondria, where it promotes cell survival by downregulating the intrinsic apoptotic pathway during conditions of oxidative stress.<ref name = "pmid25843295"/>
== Clinical significance ==
[[Mutation]]s in this gene have been associated with [[ODDD]]; [[Craniometaphyseal dysplasia autosomal dominant|craniometaphyseal dysplasia]]; [[sudden infant death syndrome]], which is linked to cardiac [[Heart arrhythmia|arrhythmia]]; [[Hallermann–Streiff syndrome]]; and heart malformations, such as [[viscero-atrial heterotaxia]].<ref name = "entrez"/><ref name = "pmid22918484"/><ref name = "pmid24434540"/><ref name="pmid14974090">{{cite journal | vauthors = Pizzuti A, Flex E, Mingarelli R, Salpietro C, Zelante L, Dallapiccola B | title = A homozygous GJA1 gene mutation causes a Hallermann-Streiff/ODDD spectrum phenotype | journal = Human Mutation | volume = 23 | issue = 3 | pages = 286 | date = Mar 2004 | pmid = 14974090 | doi = 10.1002/humu.9220 | s2cid = 13345970 | doi-access = free }}</ref> There have also been a few cases of reported hearing loss and skin disorders unrelated to ODDD.<ref name = "pmid24434540"/> Ultimately, GJA1 has low tolerance for deviations from its original sequence, with mutations resulting in loss- or gain-of-channel function that lead to disease phenotypes.<ref name = "pmid24434540"/> It is paradoxical, however, that patients with an array of somatic mutations in ''GJA1'' most often do not present with cardiac [[Heart arrhythmia|arrhythmia]]s, even though connexin-43 is the most abundant protein forming [[gap junction]]al pores in [[cardiomyocyte]]s and are essential for normal [[action potential]] propagation.<ref>{{cite journal | vauthors = Delmar M, Makita N | title = Cardiac connexins, mutations and arrhythmias | journal = Current Opinion in Cardiology | volume = 27 | issue = 3 | pages = 236–241 | date = May 2012 | pmid = 22382502 | doi = 10.1097/HCO.0b013e328352220e | s2cid = 205620477 }}</ref>
Notably, GJA1 expression has been associated with a wide variety of cancers, including [[nasopharyngeal carcinoma]], [[meningioma]], [[hemangiopericytoma]], [[liver tumor]], [[colon cancer]], [[esophageal cancer]], [[breast cancer]], [[mesothelioma]], [[glioblastoma]], [[lung cancer]], [[adrenocortical tumor]]s, [[renal cell cancer]], [[cervical carcinoma]], [[ovarian carcinoma]], [[endometrial carcinoma]], [[prostate cancer]], [[thyroid carcinoma]], and [[testicular cancer]].<ref name = "pmid22918484"/> Its role in controlling cell motility and polarity was thought to contribute to cancer development and [[metastasis]], though its role as a gap junction protein may also be involved.<ref name = "pmid22918484"/><ref name = "pmid25843295"/> Moreover, the cytoprotective effects of this protein can promote tumor cell survival in [[radiotherapy]] treatments, while silencing its gene increases radiosensitivity. As a result, GJA1 may serve as a target for improving the success of radiotherapeutic treatment of cancer.<ref name = "pmid25843295"/> As a biomarker, GJA1 could also be used to screen young males for risk of testis cancer.<ref name = "pmid22918484"/>
The [[Thyroid hormones|thyroid hormone]] [[triiodothyronine]] (T3) downregulates the expression of GJA1. This is assumed to be a key mechanism why the conduction velocity in myocardial tissue is reduced in [[thyrotoxicosis]], thereby promoting [[cardiac arrhythmia]].<ref>{{cite journal | vauthors = Müller P, Leow MK, Dietrich JW | title = Minor perturbations of thyroid homeostasis and major cardiovascular endpoints-Physiological mechanisms and clinical evidence | journal = Frontiers in Cardiovascular Medicine | volume = 9 | pages = 942971 | date = 2022 | pmid = 36046184 | doi = 10.3389/fcvm.2022.942971 | pmc = 9420854 | doi-access = free }}</ref>
Currently, only [[rotigaptide]], an antiarrhythmic peptide-based drug, and its [[Derivative (chemistry)|derivative]]s, such as danegaptide, have reached clinical trials for treating cardiac pathologies by enhancing GJA1 expression. Alternatively, drugs could target complementary connexins, such as [[Cx40]], which function similarly to GJA1. However, both approaches still require a system to target the diseased tissue to avoid inducing developmental abnormalities elsewhere.<ref name = "pmid24434540"/> Thus, a more effective approach entails designing a [[miRNA]] through [[antisense]] oligonucleotides, [[transfection]], or [[infection]] to knock down only mutant GJA1 mRNA, thus allowing the expression of [[wildtype]] GJA1 and retaining normal [[phenotype]].<ref name = "pmid22918484"/><ref name = "pmid24434540"/>
== Interactions ==
Gap junction protein, alpha 1 has been shown to [[Protein-protein interaction|interact]] with:
*[[Cx37]],<ref name = "pmid24434540"/>
*[[Cx40]],<ref name = "pmid24434540"/>
*[[Cx45]],<ref name = "pmid24434540"/>
*[[MAPK7]],<ref name="pmid12637502">{{cite journal | vauthors = Cameron SJ, Malik S, Akaike M, Lerner-Marmarosh N, Yan C, Lee JD, Abe J, Yang J | title = Regulation of epidermal growth factor-induced connexin 43 gap junction communication by big mitogen-activated protein kinase1/ERK5 but not ERK1/2 kinase activation | journal = The Journal of Biological Chemistry | volume = 278 | issue = 20 | pages = 18682–18688 | date = May 2003 | pmid = 12637502 | doi = 10.1074/jbc.M213283200 | doi-access = free }}</ref>
*[[Caveolin 1]],<ref name="pmid11980479">{{cite journal | vauthors = Schubert AL, Schubert W, Spray DC, Lisanti MP | title = Connexin family members target to lipid raft domains and interact with caveolin-1 | journal = Biochemistry | volume = 41 | issue = 18 | pages = 5754–5764 | date = May 2002 | pmid = 11980479 | doi = 10.1021/bi0121656 }}</ref>
*[[Tight junction protein 1]]<ref name="pmid9707407">{{cite journal | vauthors = Giepmans BN, Moolenaar WH | title = The gap junction protein connexin43 interacts with the second PDZ domain of the zona occludens-1 protein | journal = Current Biology | volume = 8 | issue = 16 | pages = 931–934 | year = 1998 | pmid = 9707407 | doi = 10.1016/S0960-9822(07)00375-2 | s2cid = 6434044 | doi-access = free | bibcode = 1998CBio....8..931G }}</ref>
*[[CSNK1D]],<ref name="pmid12270943">{{cite journal | vauthors = Cooper CD, Lampe PD | title = Casein kinase 1 regulates connexin-43 gap junction assembly | journal = The Journal of Biological Chemistry | volume = 277 | issue = 47 | pages = 44962–44968 | date = Nov 2002 | pmid = 12270943 | doi = 10.1074/jbc.M209427200 | doi-access = free }}</ref> and
*PTPmu ([[PTPRM]]).<ref name="pmid14681016">{{cite journal | vauthors = Giepmans BN, Feiken E, Gebbink MF, Moolenaar WH | title = Association of connexin43 with a receptor protein tyrosine phosphatase | journal = Cell Communication & Adhesion | volume = 10 | issue = 4–6 | pages = 201–205 | year = 2003 | pmid = 14681016 | doi = 10.1080/cac.10.4-6.201.205 | doi-access = free }}</ref>
== See also ==
* [[Connexin]]
* [[Hypoplastic left heart syndrome]]
== References ==
{{reflist|33em}}
== Further reading ==
{{refbegin|33em}}
*{{cite book| vauthors = Harris AL, Locke D | title = Connexins, A Guide | publisher = Springer | year = 2009 | location = New York | page = 574 | url = https://www.springer.com/978-1-934115-46-6  | isbn = 978-1-934115-46-6}}
* {{cite journal | vauthors = Saffitz JE, Laing JG, Yamada KA | title = Connexin expression and turnover : implications for cardiac excitability | journal = Circulation Research | volume = 86 | issue = 7 | pages = 723–728 | date = Apr 2000 | pmid = 10764404 | doi = 10.1161/01.res.86.7.723 | doi-access = free }}
{{refend}}
==External links==
* {{Rfam|id=RF00487|name=Connexin-43 internal ribosome entry site (IRES)}}
{{PDB Gallery|geneid=2697}}
{{Ion channels|g4}}
[[Category:Cis-regulatory RNA elements]]
[[Category:Connexins]]