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(Circulation. 2005;112:1936-1944.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Functional Roles of Ca_v1.3(_1D) Calcium Channels in Atria

Insights Gained From Gene-Targeted Null Mutant Mice

Zhao Zhang, MD, PhD; Yuxia He, MD; Dipika Tuteja, PhD; Danyan Xu, MD; Valeriy Timofeyev, PhD; Qian Zhang, MD; Kathryn A. Glatter, MD; Yanfang Xu, MD, PhD; Hee-Sup Shin, PhD; Reginald Low, MD; Nipavan Chiamvimonvat, MD

From the Division of Cardiovascular Medicine (Z.Z., X.H., D.T., D.X., V.T., Q.Z., K.A.G., Y.X., R.L., N.C.), Department of Internal Medicine, University of California, Davis; the Department of Veterans Affairs (N.C.), Northern California Health Care System, Mather, Calif; the Center for Calcium and Learning (H.-S.S.), Division of Life Sciences, Korea Institute of Science and Technology, Seoul, Korea; and the Department of Physiology (Z.Z.), Henan Medical University, Zhingzhou, China.

Correspondence to Nipavan Chiamvimonvat, Division of Cardiovascular Medicine, University of California, Davis, One Shields Ave, GBSF 6315, Davis, CA 95616. E-mail nchiamvimonvat{at}ucdavis.edu

Received January 31, 2005; revision received June 15, 2005; accepted June 27, 2005.

Background— Previous data suggest that L-type Ca²⁺ channels containing the Ca_v1.3(_1D) subunit are expressed mainly in neurons and neuroendocrine cells, whereas those containing the Ca_v1.2(_1C) subunit are found in the brain, vascular smooth muscle, and cardiac tissue. However, our previous report as well as others have shown that Ca_v1.3 Ca²⁺ channel–deficient mice (Ca_v1.3^–/–) demonstrate sinus bradycardia with a prolonged PR interval. In the present study, we extended our study to examine the role of the Ca_v1.3(_1D) Ca²⁺ channel in the atria of Ca_v1.3^–/– mice.

Methods and Results— We obtained new evidence to demonstrate that there is significant expression of Ca_v1.3 Ca²⁺ channels predominantly in the atria compared with ventricular tissues. Whole-cell L-type Ca²⁺ currents (I_Ca,L) recorded from single, isolated atrial myocytes from Ca_v1.3^–/– mice showed a significant depolarizing shift in voltage-dependent activation. In contrast, there were no significant differences in the I_Ca,L recorded from ventricular myocytes from wild-type and null mutant mice. We previously documented the hyperpolarizing shift in the voltage-dependent activation of Ca_v1.3 compared with Ca_v1.2 Ca²⁺ channel subunits in a heterologous expression system. The lack of Ca_v1.3 Ca²⁺ channels in null mutant mice would result in a depolarizing shift in the voltage-dependent activation of I_Ca,L in atrial myocytes. In addition, the Ca_v1.3-null mutant mice showed evidence of atrial arrhythmias, with inducible atrial flutter and fibrillation. We further confirmed the isoform-specific differential expression of Ca_v1.3 versus Ca_v1.2 by in situ hybridization and immunofluorescence confocal microscopy.

Conclusions— Using gene-targeted deletion of the Ca_v1.3 Ca²⁺ channel, we established the differential distribution of Ca_v1.3 Ca²⁺ channels in atrial myocytes compared with ventricles. Our data represent the first report demonstrating important functional roles for Ca_v1.3 Ca²⁺ channel in atrial tissues.

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