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@article{1203610,
author = {Spätjens, Roel L.H.M.G. and Bébarová, Markéta and Seyen, Sandrine R.M. and Lentink, Viola and Jongbloed, Roselie J. and Arens, Yvonne H.J.M. and Heijman, Jordi and Volders, Paul G.A.},
article_location = {Netherlands},
article_number = {1},
doi = {http://dx.doi.org/10.1093/cvr/cvu191},
keywords = {Long-QT syndrome type 1; I-Ks; Potassium channel; Adrenergic regulation; KCNQ1},
language = {eng},
issn = {0008-6363},
journal = {Cardiovascular Research},
title = {Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation},
volume = {104},
year = {2014}
}
TY - JOUR
ID - 1203610
AU - Spätjens, Roel L.H.M.G. - Bébarová, Markéta - Seyen, Sandrine R.M. - Lentink, Viola - Jongbloed, Roselie J. - Arens, Yvonne H.J.M. - Heijman, Jordi - Volders, Paul G.A.
PY - 2014
TI - Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation
JF - Cardiovascular Research
VL - 104
IS - 1
SP - 216-225
EP - 216-225
PB - Elsevier Science B.V.
SN - 00086363
KW - Long-QT syndrome type 1
KW - I-Ks
KW - Potassium channel
KW - Adrenergic regulation
KW - KCNQ1
N2 - Aims Mutations in KCNQ1, encoding for Kv7.1, the alpha-subunit of the I-Ks channel, cause long-QT syndrome type 1, potentially predisposing patients to ventricular tachyarrhythmias and sudden cardiac death, in particular, during elevated sympathetic tone. Here, we aim at characterizing the p.Lys557Glu (K557E) Kv7.1 mutation, identified in a Dutch kindred, at baseline and during (mimicked) increased adrenergic tone. Methods and results K557E carriers had moderate QTc prolongation that augmented significantly during exercise. I-Ks characteristics were determined after co-expressing Kv7.1-wild-type (WT) and/or K557E with minK and Yotiao in Chinese hamster ovary cells. K557E caused I-Ks loss of function with slowing of the activation kinetics, acceleration of deactivation kinetics, and a rightward shift of voltage-dependent activation. Together, these contributed to a dominant-negative reduction in I-Ks density. Confocal microscopy and western blot indicated that trafficking of K557E channels was not impaired. Stimulation of WT I-Ks by 3'-5'-cyclic adenosine monophosphate (cAMP) generated strong current up-regulation that was preserved for K557E in both hetero- and homozygosis. Accumulation of I-Ks at fast rates occurred both in WT and in K557E, but was blunted in the latter. In a computational model, K557E showed a loss of action potential shortening during beta-adrenergic stimulation, in accordance with the lack of QT shortening during exercise in patients. Conclusion K557E causes I-Ks loss of function with reduced fast rate-dependent current accumulation. cAMP-dependent stimulation of mutant I-Ks is preserved, but incapable of fully compensating for the baseline current reduction, explaining the long QT intervals at baseline and the abnormal QT accommodation during exercise in affected patients.
ER -
SPÄTJENS, Roel L.H.M.G., Markéta BÉBAROVÁ, Sandrine R.M. SEYEN, Viola LENTINK, Roselie J. JONGBLOED, Yvonne H.J.M. ARENS, Jordi HEIJMAN a Paul G.A. VOLDERS. Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation. \textit{Cardiovascular Research}. Netherlands: Elsevier Science B.V., roč.~104, č.~1, s.~216-225. ISSN~0008-6363. doi:10.1093/cvr/cvu191. 2014.
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