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.