Long-QT mutation p.K557E-Kv7.1: dominant-negative suppression of IKs, but preserved cAMP-dependent up-regulation
| Autor: | Paul G.A. Volders, Sandrine R.M. Seyen, Roselie J. Jongbloed, Viola Lentink, Markéta Bébarová, Yvonne Arens, Roel L.H.M.G. Spätjens, Jordi Heijman |
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| Přispěvatelé: | RS: CARIM - R2 - Cardiac function and failure, Genetica & Celbiologie, Ondersteunend personeel CD, MUMC+: DA KG Polikliniek (9), Cardiologie |
| Rok vydání: | 2014 |
| Předmět: |
Male
Heredity Physiology Medizin Adrenergic A Kinase Anchor Proteins Action Potentials Stimulation Dominant-Negative Mutation Second Messenger Systems chemistry.chemical_compound Electrocardiography Cyclic AMP Long-QT syndrome type 1 Potassium channel KvLQT1 KCNQ1 biology Models Cardiovascular Adrenergic beta-Agonists Middle Aged Up-Regulation Phenotype Potassium Channels Voltage-Gated KCNQ1 Potassium Channel Female Cardiology and Cardiovascular Medicine Ion Channel Gating Adenosine monophosphate Adult medicine.medical_specialty Adolescent Long QT syndrome Romano-Ward Syndrome CHO Cells Transfection QT interval Young Adult Cricetulus Dogs Physiology (medical) Internal medicine medicine Animals Humans Computer Simulation Genetic Predisposition to Disease I-Ks Adrenergic regulation medicine.disease Cytoskeletal Proteins Kinetics Endocrinology chemistry Case-Control Studies Mutation biology.protein Mutagenesis Site-Directed |
| Zdroj: | Cardiovascular Research, 104(1), 216-225. Oxford University Press |
| ISSN: | 1755-3245 0008-6363 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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