CaV1.3 L-type Ca2+ channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na+ current

Abstract

The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (Ist), a key player in SAN automaticity, is still unknown. Here we show that Ist and the L-type Ca2+ current (ICa,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that Ist is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to ICa,L activators and blockers. Both CaV1.3-mediated ICa,L and Ist were abolished in CaV1.3-deficient (CaV1.3−/−) SAN cells but the CaV1.2-mediated ICa,L current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive CaV1.2 channels (CaV1.2DHP−/−), Ist and CaV1.3-mediated ICa,L displayed overlapping sensitivity and concentration–response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies Ist, a considerable fraction of ICa,L was resistant to nifedipine inhibition in CaV1.2DHP−/− SAN cells. These findings identify CaV1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive Ist Na+ current in the SAN.