L-Type Ca(v)1.3 Calcium Channels Are Required for Beta-Adrenergic Triggered Automaticity in Dormant Mouse Sinoatrial Pacemaker Cells

Background: Sinoatrial node cells (SANC) automaticity is generated by functional association between the activity of plasmalemmal ion channels and local diastolic intracellular Ca(2+) release (LCR) from ryanodine receptors. Strikingly, most isolated SANC exhibit a “dormant” state, whereas only a fraction shows regular firing as observed in intact SAN. Recent studies showed that β-adrenergic stimulation can initiate spontaneous firing in dormant SANC, though this mechanism is not entirely understood. Methods: To investigate the role of L-type Ca(v)1.3 Ca(2+) channels in the adrenergic regulation of automaticity in dormant SANC, we used a knock-in mouse strain in which the sensitivity of L-type Ca(v)1.2 α1 subunits to dihydropyridines (DHPs) was inactivated (Ca(v)1.2(DHP−/−)), enabling the selective pharmacological inhibition of Ca(v)1.3 by DHPs. Results: In dormant SANC, β-adrenergic stimulation with isoproterenol (ISO) induced spontaneous action potentials (AP) and Ca(2+) transients, which were completely arrested with concomitant perfusion of the DHP nifedipine. In spontaneously firing SANC at baseline, Ca(v)1.3 inhibition completely reversed the effect of β-adrenergic stimulation on AP and the frequency of Ca(2+) transients. Confocal calcium imaging of SANC showed that the β-adrenergic-induced synchronization of LCRs is regulated by the activity of Ca(v)1.3 channels. Conclusions: Our study shows a novel role of Ca(v)1.3 channels in initiating and maintaining automaticity in dormant SANC upon β-adrenergic stimulation.