CaV1.3 L-type Ca2+ 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 Ca2+ 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 Ist and the L-type Ca2+ current (I-Ca,I-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,I-L activators and blockers. Both Ca(V)1.3-mediated I-Ca, L and Ist were abolished in Ca(V)1.3-deficient (Ca(V)1.3(-/-)) SAN cells but the Ca(V)1.2-mediated I-Ca,I-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,I-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,I-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.