1.A.24.1.1
Connexin 43 (gap junction α-1 protein), CX43 encoded by the GJA1 gene (transports ATP, ADP and AMP better than CX32 does; Goldberg et al., 2002). Hemichannels mediate efflux of glutathione, glutamate and other amino acids as well as ATP (Stridh et al., 2008; Kang et al., 2008). CX43 has a half life of ~3 h due to ubiquitination and lysosomal and proteasomal degradation (Leithe and Rivedal, 2007). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011). A mutant form of Connexin 43 causes Oculodentodigital dysplasia (Gabriel et al., 2011).  Suppressing the function of Cx43 promotes expression of wound healing-associated genes and hibitits scarring (Tarzemany et al. 2015).  Channel conductance and size selectivity are largely determined by pore diameter, whereas charge selectivity results from the amino-terminal domains; transitions between fully open and (multiple) closed states involves global changes in structure of the pore-forming domains (Ek Vitorín et al. 2016). The human Cx43 orthologue is almost identical to the rat protein.  It may mediate resistance against the parkinsonian toxin, 1-methyl-4-phenylpyridine (MPP⁺) which induces apoptosis in neuroblastoma cells by modulating mitochondrial apoptosis (Kim et al. 2016).  Dopamine neurons may be the target of MPP⁺ and play a role in Parkinson's disease. In humans, Cx43 plays roles in the development of the central nervous system and in the progression of glioma (Wang et al. 2017).  It interacts with and is regulated by many proteins including NOV (CCN3, IGFBP9; P48745) (Giepmans 2006). Cx43 plays roles in intercellular communication mediated by extracellular vesicles, tunnelling nanotubes and gap junctions (Ribeiro-Rodrigues et al. 2017). Phosphorylation of Cx43 leads to astrocytic coupling and apoptosis, and ultimately, to vascular regeneration in retinal ischemia. Paxillin (Pxn; 591 aas; P49023), a cytoskeletal protein involved in focal adhesion, leads to changes in connexin 43 by direct protein-protein binding, thereby influencing osteocyte gap junction elongation (Zhang et al. 2018). Regulation of Cx43 abundance involves transcriptional/post-transcriptional and translational/post-translational mechanisms that are modulated by an interplay between TGF-beta isoforms and PGE2, IL-1beta, TNF-alpha and IFN-gamma (Cheng et al. 2018). In the developing fetal human kidney, cytoplasmic expression of Cx36 was localized to nephrons in different developmental stages, glomerular vessels and collecting ducts, and of Cx43 was localized to the endothelium of glomerular and peritubular vessels, as well as to the epithelium of the proximal tubules (Ráduly et al. 2019). Mutations in the gap junction protein α1 (GPA1) gene cause oculodentodigital dysplasia (Pace et al. 2019). Expression of connexin 43 is elevated in atypical fibroxanthoma cells (Fernandez-Flores et al. 2020). Astrocytic connexin43 channels are candidate targets in epilepsy treatment (Walrave et al. 2020). Cx43 plays roles in physiological functions such as regulating cell growth, differentiation, and maintaining tissue homeostasis (Sha et al. 2020). Amyloid-beta (TC# 1.C.50) regulates connexin 43 trafficking in cultured primary astrocytes (Maulik et al. 2020). Gap junction protein Cx43 plays a role in regulating cellular function and paracrine effects of smooth muscle progenitor cells (Tien (田婷怡) et al. 2021). A serine residues in the connexin43 carboxyl tail is important for B-cell antigen receptor-mediated spreading of B-lymphocytes (Pournia et al. 2020). Connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and also as a tumor promoter (Talbot et al. 2020). Retinal astrocytes abundantly express Cx43 that forms gap junction (GJ) channels and unopposed hemichannels, and Cx43 is upregulated in retinal injuries. Astrocytic Cx43 plays a role in retinal ganglion cell (RGC) loss associated with injury (Toychiev et al. 2021). Screens for inhibitors of Cx43 hemichannel function have revealed several candidates (Soleilhac et al. 2021). The dodecameric channel is formed by the end-to-end docking of two hexameric connexons, each comprised of 24 transmembrane alpha-helices (Cheng et al. 2019). Cx43 appears to be involved in the tumorigenesis of most pituitary adenomas and have a potential therapeutic value for pituitary tumor therapy (Nunes et al. 2022). Yang et al. 2023 provided an updated understanding of connexin hemichannels and pannexin channels in response to multiple extrinsic stressors and how these activated channels and their permeable messengers participate in toxicological pathways and processes, including inflammation, oxidative damage and intracellular calcium imbalance (Yang et al. 2023). Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias (Lillo et al. 2023). Insulin docking within the open hemichannel of connexin 43 may reduce risk of amyotrophic lateral sclerosis (<Maulik et al. 2020). Gap junction protein Cx43 plays a role in regulating cellular function and paracrine effects of smooth muscle progenitor cells (Tien (田婷怡) et al. 2021). A serine residues in the connexin43 carboxyl tail is important for B-cell antigen receptor-mediated spreading of B-lymphocytes (Pournia et al. 2020). Connexin 43 plays an antagonistic role in the development of primary bone tumors as a tumor suppressor and also as a tumor promoter (Talbot et al. 2020). Retinal astrocytes abundantly express Cx43 that forms gap junction (GJ) channels and unopposed hemichannels, and Cx43 is upregulated in retinal injuries. Astrocytic Cx43 plays a role in retinal ganglion cell (RGC) loss associated with injury (Toychiev et al. 2021). Screens for inhibitors of Cx43 hemichannel function have revealed several candidates (Soleilhac et al. 2021). The dodecameric channel is formed by the end-to-end docking of two hexameric connexons, each comprised of 24 transmembrane alpha-helices (Cheng et al. 2019). Cx43 appears to be involved in the tumorigenesis of most pituitary adenomas and have a potential therapeutic value for pituitary tumor therapy (Nunes et al. 2022). Yang et al. 2023 provided an updated understanding of connexin hemichannels and pannexin channels in response to multiple extrinsic stressors and how these activated channels and their permeable messengers participate in toxicological pathways and processes, including inflammation, oxidative damage and intracellular calcium imbalance (Yang et al. 2023). Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias (Lillo et al. 2023). Insulin docking within the open hemichannel of connexin 43 may reduce risk of amyotrophic lateral sclerosis (Lehrer and Rheinstein 2023).