hERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome

McPate, M J, Zhang, H, Cordeiro, J M, Dempsey, C E, Witchel, H J and Hancox, J C (2009) hERG1a/1b heteromeric currents exhibit amplified attenuation of inactivation in variant 1 short QT syndrome. Biochemical and Biophysical Research Communications, 386 (1). pp. 111-7. ISSN 0006-291X

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Abstract

Potassium channels encoded by hERG (human ether-à-go-go-related gene) underlie the cardiac rapid delayed rectifier K+ current (IKr) and hERG mutations underpin clinically important repolarization disorders. Virtually all electrophysiological investigations of hERG mutations have studied exclusively the hERG1a isoform; however, recent evidence indicates that native IKr channels may be comprised of hERG1a together with the hERG1b variant, which has a shorter N-terminus. Here, for the first time, electrophysiological effects were studied of a gain-of-function hERG mutation (N588K; responsible for the 'SQT1' variant of the short QT syndrome) on current (I(hERG1a/1b)) carried by co-expressed hERG1a/1b channels. There were no significant effects of N588K on I(hERG1a/1b) activation or deactivation, but N588K I(hERG1a/1b) showed little inactivation up to highly positive voltages (< or = +80 mV), a more marked effect than seen for hERG1a expressed alone. I(hERG1a/1b) under action potential voltage-clamp, and the effects on this of the N588K mutation, also showed differences from those previously reported for hERG1a. The amplified attenuation of I(hERG) inactivation for the N588K mutation reported here indicates that the study of co-expressed hERG1a/1b channels should be considered when investigating clinically relevant hERG channel mutations, even if these reside outside of the N-terminus region

Item Type: Article
Keywords: Channelopathy; hERG; hERG1a/1b; hERG1b; QT interval; Rapid delayed rectifier; Short QT syndrome
Schools and Departments: Brighton and Sussex Medical School > Clinical and Laboratory Investigation
Subjects: R Medicine > RM Therapeutics. Pharmacology
R Medicine > RS Pharmacy and materia medica
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Depositing User: Patricia Butler
Date Deposited: 13 Nov 2012 10:06
Last Modified: 13 Nov 2012 10:06
URI: http://sro.sussex.ac.uk/id/eprint/42062
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