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. As a connexin, GJA1 is a component of gap junctions, which allow for gap junction intercellular communication (GJIC) between cells to regulate cell death, proliferation, and differentiation. As a result of its function, GJA1 is implicated in many biological processes, including muscle contraction, embryonic development, inflammation, and spermatogenesis, as well as diseases, including oculodentodigital dysplasia (ODDD), heart malformations, and cancers.
Structure GJA1 is a 43.0 kDa protein composed of 382 amino acids. 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. 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. 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. The connexin-43 internal ribosome entry site is an RNA element present in the 5' UTR of the mRNA of GJA1. This internal ribosome entry site (IRES) allows cap independent translation during conditions such as heat shock and stress.
Function
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. GJA1 is the most ubiquitously expressed connexin and is detected in most cell types. It is the major protein in heart gap junctions and is purported to play a crucial role in the synchronized contraction of the heart. 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. GJA1 is also largely involved in embryonic development. 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. 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. It has also been shown that uterine macrophage directly physically couple with uterine myocytes through GJA1, transferring Ca²⁺, to promote uterine muscle contraction and excitation during human labor onset. In addition, GJA1 can be found in the Leydig cells and seminiferous tubules between Sertoli cells and spermatogonia or primary spermatocytes, 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 polarity. This function has been observed in brain and heart development, as well as wound-healing in endothelial cells. 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.
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