期刊
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
卷 380, 期 1, 页码 132-137出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2009.01.052
关键词
Arrhythmia; Fibrillation; Genetics; Na(v)1.5; SCN5A; Hyperexcitability; Electrophysiology; Atria; HL-1; Cardiomyocytes
资金
- Heart and Stroke Foundations of Ontario
- Quebec
- Government of Ontario
Genetic mutations of the cardiac sodium channel (SCN5A) specific only to the phenotype of atrial fibrillation have recently been described. However, data on the biophysical properties of SCN5A variants associated with atrial fibrillation are scarce. In a mother and son with lone atrial fibrillation, we identified a novel SCN5A coding variant, K1493R, which altered a highly conserved residue in the DIII-IV linker and was located six amino acids downstream from the fast inactivation motif of sodium channels. Biophysical studies of K1493R in tsA201 cells demonstrated a significant positive shift in voltage-dependence of inactivation and a large ramp Current near resting membrane potential, indicating a gain-of-function. Enhanced cellular excitability was observed in transfected HL-1 atrial cardiomyocytes, including spontaneous action potential deplorizations and a lower threshold for action potential firing. These novel biophysical observations provide molecular evidence linking cellular hyperexcitability as a mechanism inducing vulnerability to this common arrhythmia. (C) 2009 Elsevier Inc. All rights reserved.
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