Mangoni Matteo E, Couette Brigitte, Bourinet Emmanuel, Platzer Josef, Reimer Daniel, Striessnig Jörg, Nargeot Joël
Unité Propre de Recherche 1142, Centre National de la Recherche Scientifique, Institut de Génétique Humaine, 141 Rue de la Cardonille, Montpellier Cedex 5, France.
Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5543-8. doi: 10.1073/pnas.0935295100. Epub 2003 Apr 16.
The spontaneous activity of pacemaker cells in the sino-atrial node (SAN) controls the heart rhythm and rate under physiological conditions. Pacemaker activity in SAN cells is due to the presence of the diastolic depolarization, a slow depolarization phase that drives the membrane voltage from the end of an action potential to the threshold of a new action potential. SAN cells express a wide array of ionic channels, but we have limited knowledge about their functional role in pacemaker activity and we still do not know which channels play a prominent role in the generation of the diastolic depolarization. It is thus important to provide genetic evidence linking the activity of genes coding for ionic channels to specific alterations of pacemaker activity of SAN cells. Here, we show that target inactivation of the gene coding for alpha(1D) (Ca(v)1.3) Ca(2+) channels in the mouse not only significantly slows pacemaker activity but also promotes spontaneous arrhythmia in SAN pacemaker cells. These alterations of pacemaker activity are linked to abolition of the major component of the L-type current (I(Ca,L)) activating at negative voltages. Pharmacological analysis of I(Ca,L) demonstrates that Ca(v)1.3 gene inactivation specifically abolishes I(Ca,L) in the voltage range corresponding to the diastolic depolarization. Taken together, our data demonstrate that Ca(v)1.3 channels play a major role in the generation of cardiac pacemaker activity by contributing to diastolic depolarization in SAN pacemaker cells.
在生理条件下，窦房结（SAN）中起搏细胞的自发活动控制着心律和心率。SAN细胞中的起搏活动归因于舒张期去极化的存在，这是一个缓慢的去极化阶段，它将膜电压从动作电位的末尾驱动到新动作电位的阈值。SAN细胞表达多种离子通道，但我们对它们在起搏活动中的功能作用了解有限，并且我们仍然不知道哪些通道在舒张期去极化的产生中起主要作用。因此，提供将编码离子通道的基因活性与SAN细胞起搏活动特定改变联系起来的遗传学证据很重要。在这里，我们表明，小鼠中编码α(1D)（Ca(v)1.3）钙通道的基因的靶向失活不仅显著减慢起搏活动，而且还促进SAN起搏细胞中的自发性心律失常。起搏活动的这些改变与负电压下激活的L型电流（I(Ca,L)）的主要成分的消除有关。对I(Ca,L)的药理学分析表明，Ca(v)1.3基因失活在对应于舒张期去极化的电压范围内特异性地消除了I(Ca,L)。综上所述，我们的数据表明，Ca(v)1.3通道通过促进SAN起搏细胞中的舒张期去极化，在心脏起搏活动的产生中起主要作用。
