Ca(V)1.3 L-type Ca(2+) channel contributes to the heartbeat by generating a dihydropyridine-sensitive persistent Na(+) current

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 Ca(2+) dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na(+) current (I (st)), a key player in SAN automaticity, is still unknown. Here we show that I (st) and the L-type Ca(2+) current (I (Ca,L)) share Ca(V)1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that I (st) is activated in the diastolic depolarization range, and displays Na(+) permeability and minimal inactivation and sensitivity to I (Ca,L) activators and blockers. Both Ca(V)1.3-mediated I (Ca,L) and I (st) were abolished in Ca(V)1.3-deficient (Ca(V)1.3(−/−)) SAN cells but the Ca(V)1.2-mediated I (Ca,L) current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive Ca(V)1.2 channels (Ca(V)1.2(DHP−/−)), I (st) and Ca(V)1.3-mediated I (Ca,L) displayed overlapping sensitivity and concentration–response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that Ca(V)1.3 rather than Ca(V)1.2 underlies I (st), a considerable fraction of I (Ca,L) was resistant to nifedipine inhibition in Ca(V)1.2(DHP−/−) SAN cells. These findings identify Ca(V)1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive I (st) Na(+) current in the SAN.