Mangoni Matteo E, Traboulsie Achraf, Leoni Anne-Laure, Couette Brigitte, Marger Laurine, Le Quang Khai, Kupfer Elodie, Cohen-Solal Anne, Vilar José, Shin Hee-Sup, Escande Denis, Charpentier Flavien, Nargeot Joël, Lory Philippe
Institut de Génomique Fonctionnelle, CNRS UMR5203-INSERM U661, Département de Physiologie, Université de Montpellier I, Montpellier cedex 05, F-34094, France.
Circ Res. 2006 Jun 9;98(11):1422-30. doi: 10.1161/01.RES.0000225862.14314.49. Epub 2006 May 11.
The generation of the mammalian heartbeat is a complex and vital function requiring multiple and coordinated ionic channel activities. The functional role of low-voltage activated (LVA) T-type calcium channels in the pacemaker activity of the sinoatrial node (SAN) is, to date, unresolved. Here we show that disruption of the gene coding for CaV3.1/alpha1G T-type calcium channels (cacna1g) abolishes T-type calcium current (I(Ca,T)) in isolated cells from the SAN and the atrioventricular node without affecting the L-type Ca2+ current (I(Ca,L)). By using telemetric electrocardiograms on unrestrained mice and intracardiac recordings, we find that cacna1g inactivation causes bradycardia and delays atrioventricular conduction without affecting the excitability of the right atrium. Consistently, no I(Ca,T) was detected in right atrium myocytes in both wild-type and CaV3.1(-/-) mice. Furthermore, inactivation of cacna1g significantly slowed the intrinsic in vivo heart rate, prolonged the SAN recovery time, and slowed pacemaker activity of individual SAN cells through a reduction of the slope of the diastolic depolarization. Our results demonstrate that CaV3.1/T-type Ca2+ channels contribute to SAN pacemaker activity and atrioventricular conduction.
哺乳动物心跳的产生是一项复杂且至关重要的功能，需要多种离子通道活动协同作用。迄今为止，低电压激活（LVA）的T型钙通道在窦房结（SAN）起搏活动中的功能作用尚未明确。在此，我们表明，编码CaV3.1/α1G T型钙通道（cacna1g）的基因被破坏后，会消除来自窦房结和房室结的分离细胞中的T型钙电流（I(Ca,T)），而不影响L型Ca2+电流（I(Ca,L)）。通过对不受束缚的小鼠进行遥测心电图和心内记录，我们发现cacna1g失活会导致心动过缓并延迟房室传导，但不影响右心房的兴奋性。同样，在野生型和CaV3.1(-/-)小鼠的右心房肌细胞中均未检测到I(Ca,T)。此外，cacna1g失活显著减慢了体内固有心率，延长了窦房结恢复时间，并通过降低舒张期去极化斜率减慢了单个窦房结细胞的起搏活动。我们的结果表明，CaV3.1/T型Ca2+通道对窦房结起搏活动和房室传导有贡献。
