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Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia.

http://www.ncbi.nlm.nih.gov/pubmed/12612061

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, I(Kr) 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 I(Kr) 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 I(Kr) expression in the surface membrane of adult myocytes. Knockout of ERG1 B predisposes mice to episodic sinus bradycardia.

Pubmed ID: 12612061 RIS Download

Mesh terms: Age Factors | Animals | Arrhythmia, Sinus | Bradycardia | Cation Transport Proteins | DNA-Binding Proteins | Disease Models, Animal | Electrocardiography | Ether-A-Go-Go Potassium Channels | Gene Targeting | Heart Ventricles | Ion Transport | Long QT Syndrome | Mice | Mice, Knockout | Myocardium | Patch-Clamp Techniques | Phenethylamines | Potassium | Potassium Channel Blockers | Potassium Channels | Potassium Channels, Voltage-Gated | Protein Isoforms | RNA, Messenger | Sulfonamides | Trans-Activators

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