connexin

Connexins are a family of transmembrane proteins that assemble to form gap junction channels, which directly connect the cytoplasm of adjacent cells and allow the passage of ions and small signaling molecules. Each connexin spans the membrane four times and contributes to two extracellular loops, with cytoplasmic N- and C-terminal regions. Six connexin subunits form a connexon (hemichannel); docking of two connexons from neighboring cells creates a gap junction channel that bridges the cell membranes.

Connexins are encoded by large gene families, primarily GJA (gap junction protein alpha) and GJB (gap junction protein beta). Notable members include connexin43 (GJA1), connexin26 (GJB2), connexin32 (GJB1), and connexin50 (GJA8). They can assemble into homomeric/homotypic channels or heteromeric/heterotypic channels, contributing to varied functional properties.

Physiological role involves electrical and metabolic coupling, enabling diffusion of ions and small molecules such as IP3 and cyclic nucleotides. This supports synchronized activity in heart and brain, tissue development, and homeostasis. Gating is regulated by transjunctional voltage, membrane voltage, intracellular Ca2+, pH, and post-translational modifications like phosphorylation.

Clinical relevance arises from mutations and dysregulation of connexins, which can cause inherited disorders such as nonsyndromic deafness due to GJB2 mutations, X-linked Charcot–Marie–Tooth disease from GJB1 mutations, and oculodentodigital dysplasia from GJA1 mutations. Aberrant connexin function or hemichannel activity can contribute to ischemia, inflammation, and cancer progression. Pannexins are a related family that forms channels but typically does not establish intercellular gap junctions.

Connexins are widely studied for their roles in development, tissue function, and potential as therapeutic targets, using tools such as connexin mimetic peptides and gene modulation strategies.