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

Julien Louradour (1) , Olivier Bortolotti (2) , Eleonora Torre (2) , Isabelle Bidaud (2) , Ned Lamb (3) , Anne Fernandez (3) , Jean-Yves Le Guennec (1, 4) , Matteo E. Mangoni (2) , Pietro Mesirca (2)

1 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
2 IGF - Institut de Génomique Fonctionnelle
3 IGH - Institut de génétique humaine
4 UM - Université de Montpellier

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.

Domaines: Sciences du Vivant [q-bio]

Julien Louradour, Olivier Bortolotti, Eleonora Torre, Isabelle Bidaud, Ned Lamb, et al.. L-Type Cav1.3 Calcium Channels Are Required for Beta-Adrenergic Triggered Automaticity in Dormant Mouse Sinoatrial Pacemaker Cells. Cells, 2022, 11 (7), pp.1114. ⟨10.3390/cells11071114⟩. ⟨hal-03628407⟩