Functional Roles of Ca(v)1.3 (alpha(1D)) calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice.
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.
Zhang
Zhao
Z
Department of Internal Medicine, University of California, Davis 95616, USA.
Xu
Yanfang
Y
Song
Haitao
H
Rodriguez
Jennifer
J
Tuteja
Dipika
D
Namkung
Yoon
Y
Shin
Hee-Sup
HS
Chiamvimonvat
Nipavan
N
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001283:Atrioventricular Node / Q000502:physiology / Q000503:physiopathology; D001285:Atropine / Q000494:pharmacology; D001919:Bradycardia / Q000503:physiopathology; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D004562:Electrocardiography / Q000187:drug effects; D005838:Genotype; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis; D009154:Mutation; D018408:Patch-Clamp Techniques; D011433:Propranolol / Q000494:pharmacology; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D001285:Atropine; D011433:Propranolol