Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Scientific Reports Année : 2020

Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity

Résumé

Cardiac automaticity is set by pacemaker activity of the sinus node (SAN). In addition to the ubiquitously expressed cardiac voltage-gated L-type Cav1.2 Ca2+ channel isoform, pacemaker cells within the SAN and the atrioventricular node co-express voltage-gated L-type Cav1.3 and T-type Cav3.1 Ca2+ channels (SAN-VGCCs). The role of SAN-VGCCs in automaticity is incompletely understood. We used knockout mice carrying individual genetic ablation of Cav1.3 (Cav1.3-/-) or Cav3.1 (Cav3.1-/-) channels and double mutant Cav1.3-/-/Cav3.1-/- mice expressing only Cav1.2 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 Ca2+ release, which demonstrates an important role for these channels in supporting the sarcoplasmic reticulum based "Ca2+ 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.
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hal-03013849 , version 1 (17-12-2020)

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Matthias Baudot, Eleonora Torre, Isabelle Bidaud, Julien Louradour, Angelo G Torrente, et al.. Concomitant genetic ablation of L-type Cav1.3 (α1D) and T-type Cav3.1 (α1G) Ca2+ channels disrupts heart automaticity. Scientific Reports, 2020, 10 (1), ⟨10.1038/s41598-020-76049-7⟩. ⟨hal-03013849⟩
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