Molecular biology of sodium channels and their role in cardiac arrhythmias

The:sodium channel is an integral membrane protein that plays a central rol e in conduction of the cardiac impulse in working cardiac myocytes and cell s of the His-Purkinje system. The channel has two fundamental properties, i on conduction and gating. Specific domains of the channel protein control e ach of these functions. Ion conduction describes the mechanisms of the sele ctive movement of sodium ion across the pore in the cell membrane. The sele ctivity of the channel for sodium ions is at least 10 times greater than th at for other monovalent cations; the channel does not normally conduct diva lent cations. Gating describes the opening and closing of the sodium channe l pore. Sodium channels open transiently during membrane depolarization and close by a process termed inactivation. The cardiac sodium channel protein is a multimeric complex consisting of an ct and an auxiliary P-subunit. Th e genes encoding the sodium channel have been cloned and sequenced. The cu subunit gene, SCN5A is sufficient to express a functional channel. However, beta subunit co-expression increases the level of channel expression and a lters the voltage dependence of inactivation. Mutations of the sodium chann el may result in incomplete inactivation during maintained depolarization, a decrease in the level of channel expression or acceleration of inactivati on. The resulting clinical phenotypes include long QT syndrome, type III (L QT III), Brugada syndrome, and heart block. LQT III and Brugada syndromes h ave a high case fatality rate and are best treated with an implantable defi brillator.