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Molecular and Cellular Biology, March 2003, p. 1856-1862, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.1856-1862.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Selective Knockout of Mouse ERG1 B Potassium Channel Eliminates IKr in Adult Ventricular Myocytes and Elicits Episodes of Abrupt Sinus Bradycardia

James P. Lees-Miller, Jiqing Guo, Julie R. Somers, Dan E. Roach, Robert S. Sheldon, Derrick E. Rancourt, and Henry J. Duff*

Department of Medicine, University of Calgary, Calgary, Alberta, Canada

Received 23 May 2002/ Returned for modification 1 November 2002/ Accepted 19 December 2002

The ERG1 gene encodes a family of potassium channels. Mutations in human ERG1 lead to defects in cardiac repolarization, referred to as the long QT syndrome. Through homologous recombination in mouse embryonic stem cells the ERG1 B potassium channel transcript was eliminated while the ERG1 A transcript was maintained. Heterologous expression of ERG1 isoforms had previously indicated that the deactivation time course of ERG1 B is 10-fold more rapid than that of ERG1 A. In day-18 fetal +/+ myocytes, IKr exhibited two time constants of deactivation (3,933 ± 404 and 350 ± 19 ms at -50 mV), whereas in age-matched ERG1 B-/- mice the rapid component was absent. Biexponential deactivation rates (2,039 ± 268 and 163 ± 43 ms at -50 mV) were also observed in adult +/+ myocytes. In adult ERG1 B-/- myocytes no IKr was detected. Electrocardiogram intervals were similar in +/+ and -/- mice. However, adult -/- mice manifested abrupt spontaneous episodes of sinus bradycardia (>100 ms of slowing) in 6 out of 21 mice. This phenomenon was never observed in +/+ mice (0 out of 16). We conclude that ERG1 B is necessary for IKr expression in the surface membrane of adult myocytes. Knockout of ERG1 B predisposes mice to episodic sinus bradycardia.

* Corresponding author. Mailing address: Department of Medicine, University of Calgary, 3330 Hospital Dr. NW, Calgary, Alberta, Canada T2N 4N1. Phone: (403) 220-6841. Fax: (403) 270-0313. E-mail: hduff{at}ucalgary.ca.

Molecular and Cellular Biology, March 2003, p. 1856-1862, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.1856-1862.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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