Heart automaticity in mice lacking L-type Cav1.3 and T-type Cav3.1 Ca2+ channels: Insights into the cardiac pacemaker mechanism - 26/03/18
Résumé |
Introduction |
Sino-atrial node (SAN) pacemaker activity is generated by ion channels of the plasma membrane, such as hyperpolarization-activated “funny” f-(HCN), Ca2+ channels and ryanodine receptor (RyR) – dependent Ca2+ release from the sarcoplasmic reticulum (SR). It is currently disputed whether Ca2+ release from RyRs could sustain viable pacemaker activity provided preserved SR Ca2+ content. While working myocytes express L-type Cav1.2 channels to maintain SR Ca2+ content, SAN cells express also L-type Cav1.3 and T-type Cav3.1 channels to generate pacemaking.
Objectives |
We used mutant mice carrying concomitant ablation of Cav1.3 and Cav3.1 (Cav1.3−/−/Cav3.1−/−) to study the importance of these channels in automaticity. We also investigated the role of f-HCN channels and RyR-dependent Ca2+ release in residual pacemaker activity of mutant mice.
Methods |
We employed in vivo telemetric recordings of heart rate (HR) in Cav1.3−/−, Cav3.1−/− and Cav1.3−/−/Cav3.1−/− mice. We studied the consequences of pharmacologic inhibition of f-HCN and TTX-sensitive Na+ channels in mutant mice using Langendorff perfused hearts or optical mapping (OM) of the pacemaker impulse in intact SAN preparations (SANs).
Results |
Cav ablation reduced HR in mice: Cav3.1−/− (−7.6%, n=11), Cav1.3−/− (−24.4%, n=8), Cav1.3−/−/Cav3.1−/− (−35%, n=11). In OM experiments on SANs, concomitant inhibition of f-HCN and Nav1.1 channels slowed pacemaking in wild-type (−48%, n=7) and Cav3.1−/− (−37%, n=7), while arresting automaticity in 4/6 of Cav1.3−/−, 3/6 of Cav1.3−/−/Cav3.1−/−. When present, residual pacemaking was reduced by 82%. Similar results were obtained using isolated Cav1.3−/−/Cav3.1−/− pacemaker cells were automaticity arrested in 5/9 cells tested, or was reduced by 80% in 4/9 cells.
Conclusion |
Heart automaticity is primarily generated by Cav1.3 and f-HCN channels. RyR-dependent Ca2+ release cannot sustain automaticity following concomitant targeting of Cav1.3 and f-HCN channels.
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Vol 10 - N° 2
P. 238 - avril 2018 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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