PubMed 19167345

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: Nav1.5

Title: Gain-of-function mutation of Nav1.5 in atrial fibrillation enhances cellular excitability and lowers the threshold for action potential firing.

Authors: Qiuju Li, Hai Huang, Gele Liu, Khanh Lam, Julie Rutberg, Martin S Green, David H Birnie, Robert Lemery, Mohamed Chahine, Michael H Gollob

Journal, date & volume: Biochem. Biophys. Res. Commun., 2009 Feb 27 , 380, 132-7

PubMed link:

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 depolarizations 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.