GJA1 is a 43.0 kDa protein composed of 382 amino acids.[11] 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.[12] The C-terminal tail is composed of 50 amino acids and includes post-translational modification sites, as well as binding sites for transcription 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 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.[12]
Connexin 43 distribution in the rat myocardium (gap junctions between cardiomyocytes)
As a member of the connexin family, GJA1 is a component of gap junctions, which are intercellular channels that connect adjacent cells to permit the exchange of low molecular weight molecules, such as small ions and secondary messengers, to maintain homeostasis.[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 in heart 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 short half-life (only two to four hours), indicating that the protein undergoes daily turnover in the heart and may be highly abundant or compensated with other connexins.[12]
GJA1 is also largely involved in embryonic development.[7][8] For instance, transforming growth factor-beta 1 (TGF-β1) was observed to induce GJA1 expression via the Smad and ERK1/2 signaling pathways, resulting in trophoblast cell differentiation into the placenta.[8]
Furthermore, GJA1 is expressed in many immune cells, such as eosinophils and T cells, where its gap junction function promotes the maturation and activation of these cells and, by extension, the cross-communication necessary to mount an inflammatory response.[10] It has also been shown that uterinemacrophage directly physically couple with uterine myocytes through GJA1, transferring Ca²⁺, to promote uterine muscle contraction and excitation during human labor onset.[16]
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 polarity.[9][13] This function has been observed in brain and heart development, as well as wound-healing in endothelial 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]
Currently, only rotigaptide, an antiarrhythmic peptide-based drug, and its derivatives, 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.[12] 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.[9][12]
Interactions
Gap junction protein, alpha 1 has been shown to interact with:
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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 (May 1999). "Linkage analysis narrows the critical region for oculodentodigital dysplasia to chromosome 6q22-q23". Genomics. 58 (1): 34–40. doi:10.1006/geno.1999.5814. PMID10331943.
^Fishman GI, Eddy RL, Shows TB, Rosenthal L, Leinwand LA (May 1991). "The human connexin gene family of gap junction proteins: distinct chromosomal locations but similar structures". Genomics. 10 (1): 250–256. doi:10.1016/0888-7543(91)90507-B. PMID1646158.
