Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression
of I-Ks, but preserved cAMP-dependent up-regulation

J 2014

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation

SPÄTJENS, Roel L.H.M.G.; Markéta BÉBAROVÁ; Sandrine R.M. SEYEN; Viola LENTINK; Roselie J. JONGBLOED et. al.

Basic information

Original name

Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation

Authors

SPÄTJENS, Roel L.H.M.G. (528 Netherlands); Markéta BÉBAROVÁ (203 Czech Republic, guarantor, belonging to the institution); Sandrine R.M. SEYEN (528 Netherlands); Viola LENTINK (528 Netherlands); Roselie J. JONGBLOED (528 Netherlands); Yvonne H.J.M. ARENS (528 Netherlands); Jordi HEIJMAN (276 Germany) and Paul G.A. VOLDERS (528 Netherlands)

Edition

Cardiovascular Research, Netherlands, Elsevier Science B.V. 2014, 0008-6363

Other information

Language

English

Type of outcome

Article in a journal

Field of Study

30201 Cardiac and Cardiovascular systems

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

is not subject to a state or trade secret

Impact factor

Impact factor: 5.940

RIV identification code

RIV/00216224:14110/14:00076953

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1093/cvr/cvu191

UT WoS

000343317000022

EID Scopus

2-s2.0-84913583543

Keywords in English

Long-QT syndrome type 1; I-Ks; Potassium channel; Adrenergic regulation; KCNQ1

Abstract

V originále

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.

Cite

SPÄTJENS, Roel L.H.M.G.; Markéta BÉBAROVÁ; Sandrine R.M. SEYEN; Viola LENTINK; Roselie J. JONGBLOED; Yvonne H.J.M. ARENS; Jordi HEIJMAN and Paul G.A. VOLDERS. Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation (Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation). Cardiovascular Research. Netherlands: Elsevier Science B.V., 2014, vol. 104, No 1, p. 216-225. ISSN 0008-6363. Available from: https://dx.doi.org/10.1093/cvr/cvu191.

@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 and Paul G.A. VOLDERS. Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of I-Ks, but preserved cAMP-dependent up-regulation (Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation). \textit{Cardiovascular Research}. Netherlands: Elsevier Science B.V., 2014, vol.~104, No~1, p.~216-225. ISSN~0008-6363. Available from: https://dx.doi.org/10.1093/cvr/cvu191.

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