Functional Roles of Ca v 1.3 (α 1D ) Calcium Channel in Sinoatrial Nodes

Abstract

We directly examined the role of the Ca v 1.3 (α 1D ) Ca 2+ channel in the sinoatrial (SA) node by using Ca v 1.3 Ca 2+ channel-deficient mice. A previous report has shown that the null mutant (Ca v 1.3 −/− ) mice have sinus bradycardia with a prolonged PR interval. In the present study, we show that spontaneous action potentials recorded from the SA nodes show a significant decrease in the beating frequency and rate of diastolic depolarization in Ca v 1.3 −/− mice compared with their heterozygous (Ca v 1.3 +/− ) or wild-type (WT, Ca v 1.3 +/+ ) littermates, suggesting that the deficit is intrinsic to the SA node. Whole-cell L-type Ca 2+ currents ( I Ca,L s) recorded in single isolated SA node cells from Ca v 1.3 −/− mice show a significant depolarization shift in the activation threshold. The voltage-dependent activation of Ca v 1.2 (α 1C ) versus Ca v 1.3 Ca 2+ channel subunits was directly compared by using a heterologous expression system without β coexpression. Similar to the I Ca,L recorded in the SA node of Ca v 1.3 −/− mutant mice, the Ca v 1.2 Ca 2+ channel shows a depolarization shift in the voltage-dependent activation compared with that in the Ca v 1.3 Ca 2+ channel. In summary, using gene-targeted deletion of the Ca v 1.3 Ca 2+ channel, we were able to establish a role for Ca v 1.3 Ca 2+ channels in the generation of the spontaneous action potential in SA node cells.