Format

Send to

Choose Destination
Cardiovasc Res. 2016 Mar 1;109(3):451-61. doi: 10.1093/cvr/cvw006. Epub 2016 Jan 19.

L-type Cav1.3 channels regulate ryanodine receptor-dependent Ca2+ release during sino-atrial node pacemaker activity.

Author information

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.

KEYWORDS:

Ca2+ dynamics; Cav1.3; L-type Ca2+ channels; Pacemaker activity; Sino-atrial node

PMID:
26786159
DOI:
10.1093/cvr/cvw006
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center