L-Type Cav1.3 Calcium Channels Are Required for Beta-Adrenergic Triggered Automaticity in Dormant Mouse Sinoatrial Pacemaker Cells.

ABSTRACT

BACKGROUND: Sinoatrial node cells (SANC) automaticity is generated by functional association between the activity of plasmalemmal ion channels and local diastolic intracellular Ca2+ 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 ß-adrenergic stimulation can initiate spontaneous firing in dormant SANC, though this mechanism is not entirely understood. METHODS: To investigate the role of L-type Cav1.3 Ca2+ channels in the adrenergic regulation of automaticity in dormant SANC, we used a knock-in mouse strain in which the sensitivity of L-type Cav1.2 α1 subunits to dihydropyridines (DHPs) was inactivated (Cav1.2DHP-/-), enabling the selective pharmacological inhibition of Cav1.3 by DHPs. RESULTS: In dormant SANC, ß-adrenergic stimulation with isoproterenol (ISO) induced spontaneous action potentials (AP) and Ca2+ transients, which were completely arrested with concomitant perfusion of the DHP nifedipine. In spontaneously firing SANC at baseline, Cav1.3 inhibition completely reversed the effect of ß-adrenergic stimulation on AP and the frequency of Ca2+ transients. Confocal calcium imaging of SANC showed that the ß-adrenergic-induced synchronization of LCRs is regulated by the activity of Cav1.3 channels. CONCLUSIONS: Our study shows a novel role of Cav1.3 channels in initiating and maintaining automaticity in dormant SANC upon ß-adrenergic stimulation.