Functional Roles of Ca(v)1.3 (alpha(1D)) calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice.

Abstract

We directly examined the role of the Ca(v)1.3 (alpha(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 (alpha(1C)) versus Ca(v)1.3 Ca(2+) channel subunits was directly compared by using a heterologous expression system without beta 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.