Concomitant genetic ablation of L-type Ca v 1.3 (α 1D ) and T-type Ca v 3.1 (α 1G ) Ca 2+ channels disrupts heart automaticity.

Autor: Baudot M; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Torre E; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France.; Department of Biotechnology and Biosciences, Università Degli Studi di Milano-Bicocca, Milan, Italy., Bidaud I; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Louradour J; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Torrente AG; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Fossier L; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Talssi L; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Nargeot J; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Barrère-Lemaire S; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France.; LabEx ICST, Montpellier, France., Mesirca P; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France. Pietro.Mesirca@igf.cnrs.fr.; LabEx ICST, Montpellier, France. Pietro.Mesirca@igf.cnrs.fr., Mangoni ME; Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, Inserm, 141, rue de la cardonille, 34094, Montpellier, France. matteo.mangoni@igf.cnrs.fr.; LabEx ICST, Montpellier, France. matteo.mangoni@igf.cnrs.fr.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2020 Nov 03; Vol. 10 (1), pp. 18906. Date of Electronic Publication: 2020 Nov 03.
DOI: 10.1038/s41598-020-76049-7
Abstrakt: Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Ca v 1.2 Ca 2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Ca v 1.3 and T-type Ca v 3.1 Ca 2+ channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Ca v 1.3 (Ca v 1.3 -/- ) or Ca v 3.1 (Ca v 3.1 -/- ) channels and double mutant Ca v 1.3 -/- /Ca v 3.1 -/- mice expressing only Ca v 1.2 channels. We show that concomitant loss of SAN-VGCCs prevents physiological SAN automaticity, blocks impulse conduction and compromises ventricular rhythmicity. Coexpression of SAN-VGCCs is necessary for impulse formation in the central SAN. In mice lacking SAN-VGCCs, residual pacemaker activity is predominantly generated in peripheral nodal and extranodal sites by f-channels and TTX-sensitive Na + channels. In beating SAN cells, ablation of SAN-VGCCs disrupted late diastolic local intracellular Ca 2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based "Ca 2+ clock" mechanism during normal pacemaking. These data implicate an underappreciated role for co-expression of SAN-VGCCs in heart automaticity and define an integral role for these channels in mechanisms that control the heartbeat.
Databáze: MEDLINE
Externí odkaz: