Cx40

Cx40, or connexin 40, is a gap junction protein encoded by the GJA5 gene in humans. It belongs to the connexin family and forms hexameric hemichannels (connexons) that dock with connexons on neighboring cells to create gap junction channels, enabling direct cytoplasmic communication between adjacent cells.

In the heart, Cx40 is prominently expressed in atrial myocytes and parts of the cardiac conduction system, including the sinoatrial and atrioventricular nodes. It contributes to fast atrial conduction velocity and synchronized atrial contraction. Cx40 is also present in endothelial cells of large arteries, where it participates in coordinating vascular tone and responses to shear stress. Through gap junctional coupling, Cx40 supports electrical conduction and metabolic exchange between neighboring cells.

Structurally, Cx40 proteins span four transmembrane domains and have intracellular N- and C-termini and a cytoplasmic loop. Regulation of Cx40 involves transcriptional control, post-translational modifications such as phosphorylation, and trafficking to and from gap junction plaques. The channels exhibit selective permeability for ions and small metabolites and can form homomeric or heteromeric channels with other connexins, influencing their biophysical properties.

Clinical significance includes associations between GJA5 mutations and atrial fibrillation and various conduction disorders. In mouse models, Cx40 deficiency leads to slowed atrial conduction, altered atrial refractoriness, and increased susceptibility to atrial arrhythmias. Endothelial Cx40 alterations have been linked to impaired flow-mediated vasodilation and vascular dysfunction.

Cx40 is an essential component of intercellular communication in cardiac and vascular tissues, contributing to electrical synchronization in the heart and coordinated vascular responses in blood vessels.