GJA5 (gap junction protein alpha 5, connexin 40) encodes a transmembrane protein that forms gap junction channels enabling low-resistance intercellular communication essential for coordinated cardiac electrical activity 1. The protein assembles into connexon pairs that allow rapid propagation of action potentials through the myocardium, supporting normal conduction velocity in atria and ventricles 2. GJA5 expression is regulated by pulsatile hemodynamic shear stress and is specifically restricted to arterial endothelium, where it promotes flow-driven arteriogenesis and vascular remodeling 1. During cardiac pressure overload, GJA5 expression is downregulated alongside other rapid conduction genes, contributing to atrial electrical remodeling and arrhythmia susceptibility 3. Clinically, GJA5 mutations cause atrial fibrillation through impaired gap junction trafficking, reduced channel function, or pathological hemichannel gain-of-function 2. Polymorphisms in GJA5 are associated with sudden cardiac death risk in women 4 and essential hypertension 5. The gene also participates in vascular wall remodeling during atherosclerosis, with connexin-based therapeutic strategies under investigation 6. Additionally, GJA5 expression is regulated by NOTCH1 signaling in valve endothelium, linking gap junction function to vascular calcification prevention 7.