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, 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.

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

• Original 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
• Keywords in English: Long-QT syndrome type 1; I-Ks; Potassium channel; Adrenergic regulation; KCNQ1
• Tags: EL OK
• Tags: International impact, Reviewed

Abstract

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.