1.A.24.1.16
Connexin-43, Cx43, or Gap Junction α-1 protein, GJA1, of 382 aas and 4 TMSs in a 2 + 2 TMS arrangement.  Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells, contributing to osteoarthritis progression (Varela-Eirín et al. 2022). It is 98% identical to the rat ortholog (TC# 1.A.24.1.1).  Cx43 expression is highly sensitive to oxidative distress, leading to reduced expression (Wahl et al. 2022). This effect can be efficiently prevented by the glutathione peroxidase mimetic ebselen. Cx43 expression is tightly regulated by miR-1, which is activated by tachypacing-induced oxidative distress. In light of the high arrhythmogenic potential of altered Cx43 expression, miR-1 may be a target for pharmacological interventions to prevent the maladaptive remodeling processes during chronic distress in the heart (Wahl et al. 2022). Cx43 hemichannels can reversibly transport NAD⁺ and cyclic ADP-ribose, the latter which acts on cytoplasmic ryanodine receptors (RyRs) (Astigiano et al. 2022). Connexin 43 hemichannels regulate mitochondrial ATP generation, mobilization, and mitochondrial homeostasis against oxidative stress (Zhang et al. 2022). Cx43 and Cx32 catalyze ATP release from cells (Tovar et al. 2023). Jiang et al. 2023 have summarized the association between Cx43 and neuroinflammation, the cornerstones linking inflammation and depression, and Cx43 abnormalities in depression. The orally delivered Connexin43 hemichannel blocker, tonabersat, inhibits vascular breakdown and inflammasome activation in a mouse model of diabetic retinopathy suggesting that tonabersat may be a safe and effective treatment for DR (Mugisho et al. 2023). Conformational changes in the human Cx43/GJA1 gap junction channel have been visualized using cryo-EM (Lee et al. 2023). Simvastatin is an adjuvant in doxorubicin anticancer therapy. Its antioxidant and antiapoptotic activityies showed that Simvastatin interferes with expression and cellular localization of Cx43 that is widely involved in cardioprotection (Pecoraro et al. 2023). CX43 down-regulation promotes cell aggressiveness and 5-fluorouracil-resistance by attenuating cell stiffness in colorectal carcinoma (Han et al. 2023). The structure of a human Cx43 GJC has been solved by cryo-EM and single particle analysis at 2.26 Å resolution. The pore region of Cx43 GJC features several lipid-like densities per Cx43 monomer, located close to a putative lateral access site at the monomer boundary. A previously undescribed conformation on the cytosolic side of the pore, formed by the N-terminal domain and the transmembrane helix 2 of Cx43 are stabilized by a small molecule. Structures of the Cx43 GJC and hemichannels (HCs) in nanodiscs reveal a similar gate arrangement (Qi et al. 2023). Opening of Cx43-formed hemichannels mediates the Ca²⁺ signaling associated with endothelial cell migration (Espinoza and Figueroa 2023). The roles of Cx43 in disease development from the perspective of subcellular localization have been summarized (Xiong et al. 2023). Opening of Cx43-formed hemichannels mediates the Ca²⁺ signaling associated with endothelial cell migration (Espinoza and Figueroa 2023).   Targeting Cx43 reduces the severity of pressure ulcer progression (Kwek et al. 2023).  Multiple sclerosis (MS) is a neurodegenerative disease marked by chronic neuroinflammation thought to be mediated by the inflammasome pathway. Connexin 43 (Cx43) hemichannels contribute to the activation of the inflammasome through the release of adenosine triphosphate (ATP) inflammasome activation signals.  Tonabersat significantly reduces disease progression in an experimental mouse model of multiple sclerosis (Kwakowsky et al. 2023).  The E3 ubiquitin ligase ITCH negatively regulates intercellular communication via gap junctions by targeting connexin43 for lysosomal degradation (Totland et al. 2024). Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage (Gómez et al. 2024).