Angelo Giovanni Torrente1, Pietro Mesirca2, Patricia Neco3, Riccardo Rizzetto2, Stefan Dubel2, Christian Barrere2, Martina Sinegger-Brauns4, Joerg Striessnig4, Sylvain Richard5, Joël Nargeot2, Ana Maria Gomez3, Matteo Elia Mangoni1. 1. Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34000, France INSERM, U1191, Montpellier F-34000, France Université de Montpellier, UMR-5203, Montpellier F-34000, France matteo.mangoni@igf.cnrs.fr angelotorrente@hotmail.com. 2. Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier F-34000, France INSERM, U1191, Montpellier F-34000, France Université de Montpellier, UMR-5203, Montpellier F-34000, France. 3. UMR-S 1180, Inserm, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France Department of Pharmacology and Toxicology, Institute of Pharmacy. 4. Department of Pharmacology and Toxicology, Institute of Pharmacy Center for Molecular Biosciences, University of Innsbruck, Innsbruck, Austria. 5. INSERM, U1046, Montpellier, France CNRS UMR 9214, PhyMedExp, University of Montpellier, France.
Abstract
AIMS: Sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of intracellular Ca(2+) ([Ca(2+)]i) dynamics during SAN pacemaker activity. Nevertheless, the functional role of voltage-dependent L-type Ca(2+) channels in controlling SAN [Ca(2+)]i release is largely unexplored. Since Cav1.3 is the predominant L-type Ca(2+) channel isoform in SAN cells, we studied [Ca(2+)]i dynamics in isolated cells and ex vivo SAN preparations explanted from wild-type (WT) and Cav1.3 knockout (KO) mice (Cav1.3(-/-)). METHODS AND RESULTS: We found that Cav1.3 deficiency strongly impaired [Ca(2+)]i dynamics, reducing the frequency of local [Ca(2+)]i release events and preventing their synchronization. This impairment inhibited the generation of Ca(2+) transients and delayed spontaneous activity. We also used action potentials recorded in WT SAN cells as voltage-clamp commands for Cav1.3(-/-) cells. Although these experiments showed abolished Ca(2+) entry through L-type Ca(2+) channels in the diastolic depolarization range of KO SAN cells, their sarcoplasmic reticulum Ca(2+) load remained normal. β-Adrenergic stimulation enhanced pacemaking of both genotypes, though, Cav1.3(-/-) SAN cells remained slower than WT. Conversely, we rescued pacemaker activity in Cav1.3(-/-) SAN cells and intact tissues through caffeine-mediated stimulation of Ca(2+)-induced Ca(2+) release. CONCLUSIONS: Cav1.3 channels play a critical role in the regulation of [Ca(2+)]i dynamics, providing an unanticipated mechanism for triggering local [Ca(2+)]i releases and thereby controlling pacemaker activity. Our study also provides an additional pathophysiological mechanism for congenital SAN dysfunction and heart block linked to Cav1.3 loss of function in humans. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of intracellular Ca(2+) ([Ca(2+)]i) dynamics during SAN pacemaker activity. Nevertheless, the functional role of voltage-dependent L-type Ca(2+) channels in controlling SAN [Ca(2+)]i release is largely unexplored. Since Cav1.3 is the predominant L-type Ca(2+) channel isoform in SAN cells, we studied [Ca(2+)]i dynamics in isolated cells and ex vivo SAN preparations explanted from wild-type (WT) and Cav1.3 knockout (KO) mice (Cav1.3(-/-)). METHODS AND RESULTS: We found that Cav1.3deficiency strongly impaired [Ca(2+)]i dynamics, reducing the frequency of local [Ca(2+)]i release events and preventing their synchronization. This impairment inhibited the generation of Ca(2+) transients and delayed spontaneous activity. We also used action potentials recorded in WT SAN cells as voltage-clamp commands for Cav1.3(-/-) cells. Although these experiments showed abolished Ca(2+) entry through L-type Ca(2+) channels in the diastolic depolarization range of KO SAN cells, their sarcoplasmic reticulum Ca(2+) load remained normal. β-Adrenergic stimulation enhanced pacemaking of both genotypes, though, Cav1.3(-/-) SAN cells remained slower than WT. Conversely, we rescued pacemaker activity in Cav1.3(-/-) SAN cells and intact tissues through caffeine-mediated stimulation of Ca(2+)-induced Ca(2+) release. CONCLUSIONS:Cav1.3 channels play a critical role in the regulation of [Ca(2+)]i dynamics, providing an unanticipated mechanism for triggering local [Ca(2+)]i releases and thereby controlling pacemaker activity. Our study also provides an additional pathophysiological mechanism for congenital SAN dysfunction and heart block linked to Cav1.3 loss of function in humans. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Yue Yi Wang; Pietro Mesirca; Elena Marqués-Sulé; Alexandra Zahradnikova; Olivier Villejoubert; Pilar D'Ocon; Cristina Ruiz; Diana Domingo; Esther Zorio; Matteo E Mangoni; Jean-Pierre Benitah; Ana María Gómez Journal: JCI Insight Date: 2017-04-20
Authors: Claudia M Moreno; Rose E Dixon; Sendoa Tajada; Can Yuan; Ximena Opitz-Araya; Marc D Binder; Luis F Santana Journal: Elife Date: 2016-05-17 Impact factor: 8.140
Authors: Pietro Mesirca; Vadim V Fedorov; Thomas J Hund; Angelo G Torrente; Isabelle Bidaud; Peter J Mohler; Matteo E Mangoni Journal: Annu Rev Pharmacol Toxicol Date: 2020-10-05 Impact factor: 13.820