Connexin 40 in atrial fibrillation: pathophysiological roles and regulatory mechanisms

Atrial fibrillation (AF), the most prevalent clinical atrial arrhythmia, arises from complex dysregulation of multicellular signalling pathways and molecular networks. Recent advances in cardiac electrophysiology have identified the atrial-specific gap junction protein Connexin 40 (Cx40) as a pivotal regulator of intercellular communication and cardiac electrical synchronization in AF pathogenesis. Aberrant Cx40 expression significantly disrupts atrial electrical conduction, yet its precise regulatory mechanisms remain incompletely understood. This review systematically examines the multifaceted roles of Cx40 in AF development, particularly focusing on how Cx40 genetic polymorphisms influence cardiac electrophysiology and promote atrial structural remodelling. Furthermore, we elucidate the ubiquitination-mediated protein degradation pathways governing Cx40 stability. These insights advance our understanding of AF pathophysiology and highlight potential therapeutic targets for precision arrhythmia management.