Connexin43 and NaV1.5: Partners in crime?

Abstract

c c i m t h s t Propagation of the electrical impulse through the myocardium depends on the critical interplay of various factors, including excitability, cell-to-cell coupling, and tissue architecture. Although intercellular transfer of current through gap junctions is essential for proper impulse propagation, mild-tomoderate reduction of the ventricular gap junctional protein connexin43 (Cx43) is generally well tolerated by the normal, uncompromised heart. Indeed, transgenic mice with 50% reduction of Cx43 display normal ventricular activation patterns and conduction velocities, while conduction slowing and increased arrhythmia susceptibility is observed only in those mice in which Cx43 levels are reduced by more than 90%. In the ischemic and failing myocardium, however, heterogeneous reduction in Cx43 expression contributes to conduction abnormalities and arrhythmogenesis. Thus, Cx43 reduction appears to be detrimental only when severely or heterogeneously suppressed or in the presence of additional contributing factors, such as structural abnormalities and/or reduced tissue excitability. This concept is further highlighted in the current issue of HeartRhythm by the study of Jansen et al on entricular arrhythmias in mice with a postnatally induced evere reduction in Cx43. More importantly, this study also mplicates a modulatory effect of Cx43 on the expression and unction of cardiac sodium channels, further underlining the ncreasing complex role of connexins. In recent years, it has become increasingly clear that conexins are not isolated entities simply involved in the conducion of ions and signals between adjacent myocytes, but that hey also physically and functionally interact with other proeins within the cell. A large number of connexin interacting roteins have now been identified, including structural proeins, cytoskeletal components, and adhesion molecules. These interacting proteins are incorporated into a macromolecular complex through which connexins can exert regulatory effects on intracellular signaling, cytoskeletal organization, and cell adhesion. Desmosomal proteins such as plakoglobin and