| Connexin43 | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 connexin 43 carboxyl terminal domain | |||||||||
| Identifiers | |||||||||
| Symbol | Connexin43 | ||||||||
| Pfam | PF03508 | ||||||||
| InterPro | IPR013124 | ||||||||
| TCDB | 1.A.24 | ||||||||
| |||||||||
Gap junction alpha-1 protein (GJA1), also known asconnexin 43 (Cx43), is aprotein that in humans is encoded by theGJA1gene on chromosome 6.[5][6][7] As aconnexin, GJA1 is a component ofgap junctions, which allow for gap junctionintercellular communication (GJIC) betweencells to regulatecell death,proliferation, anddifferentiation.[8] As a result of its function, GJA1 is implicated in many biological processes, includingmuscle contraction,embryonic development,inflammation, andspermatogenesis, as well asdiseases, includingoculodentodigital dysplasia (ODDD), heart malformations, andcancers.[7][9][10]
GJA1 is a 43.0 kDaprotein composed of 382amino acids.[11] GJA1 contains a longC-terminal tail, anN-terminal domain, and multipletransmembrane domains. The protein passes through thephospholipid bilayer four times, leaving its C- and N-terminals exposed to thecytoplasm.[12] The C-terminal tail is composed of 50amino acids and includespost-translational modification sites, as well as binding sites fortranscription factors,cytoskeleton elements, and other proteins.[12][13] As a result, the C-terminal tail is central to functions such as regulating pH gating and channel assembly. Notably, the DNA region of theGJA1 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 theextracellular loops facilitate proper channel docking. Moreover, two extracellular loops form disulfide bonds that interact with two hexamers to form a complete gap junction channel.[12]
Theconnexin-43 internal ribosome entry site is anRNA element present in the5' UTR of themRNA of GJA1. Thisinternal ribosome entry site (IRES) allows cap independenttranslation during conditions such asheat shock and stress.[14]
| Connexin-43 internal ribosome entry site (IRES) | |
|---|---|
 Predictedsecondary structure andsequence conservation of IRES_Cx43 | |
| Identifiers | |
| Symbol | IRES_Cx43 |
| Rfam | RF00487 |
| Other data | |
| RNA type | Cis-reg;IRES |
| Domain | Eukaryota |
| GO | GO:0043022 |
| SO | SO:0000243 |
| PDB structures | PDBe |
As a member of theconnexin family, GJA1 is a component ofgap junctions, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as smallions andsecondary messengers, to maintainhomeostasis.[7][12][15]
GJA1 is the most ubiquitously expressed connexin and is detected in most cell types.[7][9][12]It is the major protein inheart gap junctions and is purported to play a crucial role in the synchronized contraction of the heart.[7] Despite its key role in the heart and other vital organs, GJA1 has a shorthalf-life (only two to four hours), indicating that the protein undergoes dailyturnover in the heart and may be highly abundant or compensated with other connexins.[12] GJA1 is also largely involved inembryonic development.[7][8] For instance,transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via theSmad andERK1/2signaling pathways, resulting introphoblast cell differentiation into theplacenta.[8]
Furthermore, GJA1 is expressed in manyimmune cells, such aseosinophils andT cells, where its gap junction function promotes the maturation and activation of these cells and, by extension, the cross-communication necessary to mount aninflammatory response.[10] It has also been shown thatuterinemacrophage directly physically couple with uterinemyocytes through GJA1, transferringCa²⁺, to promote uterine muscle contraction and excitation during humanlabor onset.[16]
In addition, GJA1 can be found in theLeydig cells andseminiferous tubules betweenSertoli cells andspermatogonia orprimary spermatocytes, where it plays a key role inspermatogenesis andtestis development through controlling thetight junction proteins in theblood-testis barrier.
While it is a channel protein, GJA1 can also perform channel-independent functions. In thecytoplasm, the protein regulates themicrotubule network and, by extension,cell migration andpolarity.[9][13] This function has been observed inbrain and heart development, as well as wound-healing inendothelial cells.[13] 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.[15]
Mutations in this gene have been associated withODDD;craniometaphyseal dysplasia;sudden infant death syndrome, which is linked to cardiacarrhythmia;Hallermann–Streiff syndrome; and heart malformations, such asviscero-atrial heterotaxia.[7][9][12][17] There have also been a few cases of reported hearing loss and skin disorders unrelated to ODDD.[12] 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.[12] It is paradoxical, however, that patients with an array of somatic mutations inGJA1 most often do not present with cardiacarrhythmias, even though connexin-43 is the most abundant protein forminggap junctional pores incardiomyocytes and are essential for normalaction potential propagation.[18]
Notably, GJA1 expression has been associated with a wide variety of cancers, includingnasopharyngeal carcinoma,meningioma,hemangiopericytoma,liver tumor,colon cancer,esophageal cancer,breast cancer,mesothelioma,glioblastoma,lung cancer,adrenocortical tumors,renal cell cancer,cervical carcinoma,ovarian carcinoma,endometrial carcinoma,prostate cancer,thyroid carcinoma, andtesticular cancer.[9] Its role in controlling cell motility and polarity was thought to contribute to cancer development andmetastasis, though its role as a gap junction protein may also be involved.[9][15] Moreover, the cytoprotective effects of this protein can promote tumor cell survival inradiotherapy 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.[15] As a biomarker, GJA1 could also be used to screen young males for risk of testis cancer.[9]
Thethyroid hormonetriiodothyronine (T3) downregulates the expression of GJA1. This is assumed to be a key mechanism why the conduction velocity in myocardial tissue is reduced inthyrotoxicosis, thereby promotingcardiac arrhythmia.[19]
Currently, onlyrotigaptide, an antiarrhythmic peptide-based drug, and itsderivatives, such as danegaptide, have reached clinical trials for treating cardiac pathologies by enhancing GJA1 expression. Alternatively, drugs could target complementary connexins, such asCx40, which function similarly to GJA1. However, both approaches still require a system to target the diseased tissue to avoid inducing developmental abnormalities elsewhere.[12] Thus, a more effective approach entails designing amiRNA throughantisense oligonucleotides,transfection, orinfection to knock down only mutant GJA1 mRNA, thus allowing the expression ofwildtype GJA1 and retaining normalphenotype.[9][12]
Gap junction protein, alpha 1 has been shown tointeract with:
