Neuronal sodium channels: emerging components of the nano-machinery of cardiac calcium cycling.

Excitation-contraction coupling is the bridge between cardiac electrical activation and mechanical contraction. It is driven by the influx of Ca2+ across the sarcolemma triggering Ca2+ release from the sarcoplasmic reticulum (SR) - a process termed Ca2+ -induced Ca2+ release (CICR) - followed by re-sequestration of Ca2+ into the SR. The Na+ /Ca2+ exchanger inextricably couples the cycling of Ca2+ and Na+ in cardiac myocytes. Thus, influx of Na+ via voltage-gated Na+ channels (NaV ) has emerged as an important regulator of CICR both in health and in disease. Recent insights into the subcellular distribution of cardiac and neuronal NaV isoforms and their ultrastructural milieu have important implications for the roles of these channels in mediating Ca2+ -driven arrhythmias. This review will discuss functional insights into the role of neuronal NaV isoforms vis-à-vis cardiac NaV s in triggering such arrhythmias and their potential as therapeutic targets in the context of the aforementioned structural observations.