Heart automaticity in mice lacking L-type Cav1.3 and T-type Cav3.1 Ca2+ channels: Insights into the cardiac pacemaker mechanism
Introduction Sino-atrial node (SAN) pacemaker activity is generated by ion channels of the plasma membrane, such as hyperpolarization-activated “funny” f-(HCN), Ca 2+ channels and ryanodine receptor (RyR) – dependent Ca 2+ release from the sarcoplasmic reticulum (SR). It is currently disputed whether Ca 2+ release from RyRs could sustain viable pacemaker activity provided preserved SR Ca 2+ content. While working myocytes express L-type Ca v 1.2 channels to maintain SR Ca 2+ content, SAN cells express also L-type Ca v 1.3 and T-type Ca v 3.1 channels to generate pacemaking. Objectives We used mutant mice carrying concomitant ablation of Ca v 1.3 and Ca v 3.1 (Ca v 1.3 −/− /Ca v 3.1 −/− ) to study the importance of these channels in automaticity. We also investigated the role of f-HCN channels and RyR-dependent Ca 2+ release in residual pacemaker activity of mutant mice. Methods We employed in vivo telemetric recordings of heart rate (HR) in Ca v 1.3 −/− , Ca v 3.1 −/− and Ca v 1.3 −/− /Ca v 3.1 −/− 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 Ca v ablation reduced HR in mice: Ca v 3.1 −/− (−7.6%, n = 11), Ca v 1.3 −/− (−24.4%, n = 8), Ca v 1.3 −/− /Ca v 3.1 −/− (−35%, n = 11). In OM experiments on SANs, concomitant inhibition of f-HCN and Na v 1.1 channels slowed pacemaking in wild-type (−48%, n = 7) and Ca v 3.1 −/− (−37%, n = 7), while arresting automaticity in 4/6 of Ca v 1.3 −/− , 3/6 of Ca v 1.3 −/− /Ca v 3.1 −/− . When present, residual pacemaking was reduced by 82%. Similar results were obtained using isolated Ca v 1.3 −/− /Ca v 3.1 −/− 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 Ca v 1.3 and f-HCN channels. RyR-dependent Ca 2+ release cannot sustain automaticity following concomitant targeting of Ca v 1.3 and f-HCN channels.
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