Cell biology

Neuroscience

Biology

Diastolic depolarization

Calcium

Cognition

Endocrinology

Receptor

Cardiology

Stimulation

Biochemistry

Computer science

Sinoatrial node

Heart rate

Ryanodine receptor

Adrenergic receptor

Automaticity

Intracellular

Nifedipine

Blood pressure

Internal medicine

Medicine

Chemistry

Programming language

BETA (programming language)

Biophysics

Cells

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 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 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, β-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 β-adrenergic stimulation on AP and the frequency of Ca2+ transients. Confocal calcium imaging of SANC showed that the β-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 β-adrenergic stimulation.

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