L-Type Cav1.3 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 Ca2+ release (LCR) from ryanodine receptors. Strikingly, most isolated SANC exhibit a “dormant” state, whereas only a fract...

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Published in:Cells (Basel, Switzerland) Switzerland), 2022-04, Vol.11 (7), p.1114
Main Authors: Louradour, Julien, Bortolotti, Olivier, Torre, Eleonora, Bidaud, Isabelle, Lamb, Ned, Fernandez, Anne, Le Guennec, Jean-Yves, Mangoni, Matteo E., Mesirca, Pietro
Format: Article
Language:English
Subjects:
adrenergic regulation
Automation
Calcium (intracellular)
Calcium channels
Calcium channels (L-type)
Calcium channels (voltage-gated)
Calcium imaging
cardiac pacemaker activity
Cav1.3 channels
Glucose
Ion channels
Kinases
Laboratory animals
Life Sciences
Nifedipine
Pacemakers
Perfusion
Ryanodine receptors
Synchronization
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Summary: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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells11071114