TY - JOUR

T1 - Biophysical characterization of the short QT mutation hERG-N588K reveals a mixed gain-and loss-of-function

AU - Grunnet, M.

AU - Diness, T.G.

AU - Hansen, R.S.

AU - Olesen, Søren-Peter

N1 - Keywords: Action Potentials; Amino Acid Substitution; Animals; Arrhythmias, Cardiac; Asparagine; Biophysical Phenomena; Cell Line; Ether-A-Go-Go Potassium Channels; Humans; Ion Channel Gating; Lysine; Mutant Proteins; Mutation; Temperature; Time Factors; Xenopus

PY - 2008

Y1 - 2008

N2 - The short QT syndrome is a newly discovered pro-arrhythmic condition, which may cause ventricular fibrillation and sudden death. Short QT can originate from the apparent gain-of-function mutation N588K in the hERG potassium channel that conducts repolarising I(Kr) current. The present study describes a profound biophysical characterization of HERG-N588K revealing both loss-of-function and gain-of-function properties of the mutant. Experiments were conducted after heterologous expression in both Xenopus laevis oocytes and mammalian cells and at both room temperature and at 37 degrees C. Also the impact of the beta-subunits KCNE2 was investigated. The most prominent loss-of-function property of HERG-N588K was reduced tail currents but also the activation properties was compromised. Based on these biophysical results we suggest that the general view of HERG-N588K being a gain-of-function is modified to a mixed gain- and loss-of-function mutation. This might also have impact on the pathological picture of the HERG-N588K channels ability to trigger arrhythmic events.

AB - The short QT syndrome is a newly discovered pro-arrhythmic condition, which may cause ventricular fibrillation and sudden death. Short QT can originate from the apparent gain-of-function mutation N588K in the hERG potassium channel that conducts repolarising I(Kr) current. The present study describes a profound biophysical characterization of HERG-N588K revealing both loss-of-function and gain-of-function properties of the mutant. Experiments were conducted after heterologous expression in both Xenopus laevis oocytes and mammalian cells and at both room temperature and at 37 degrees C. Also the impact of the beta-subunits KCNE2 was investigated. The most prominent loss-of-function property of HERG-N588K was reduced tail currents but also the activation properties was compromised. Based on these biophysical results we suggest that the general view of HERG-N588K being a gain-of-function is modified to a mixed gain- and loss-of-function mutation. This might also have impact on the pathological picture of the HERG-N588K channels ability to trigger arrhythmic events.

U2 - 10.1159/000185545

DO - 10.1159/000185545

M3 - Journal article

C2 - 19088443

VL - 22

SP - 611

EP - 624

JO - Cellular Physiology and Biochemistry

JF - Cellular Physiology and Biochemistry

SN - 1015-8987

IS - 5-6

ER -