Cardiac Sodium Channel Nav1.5 Mechanosensitivity is Inhibited by Ranolazine
The cardiac action potential (AP) is initiated by the depolarizing inward sodium current (INa). The pore-forming subunit of the cardiac sodium channel, Nav1.5, is the main ion channel that conducts INa in cardiac cells. Despite the large number of studies investigating Nav1.5, year after year, we are still learning new aspects regarding its roles in normal cardiac function and in diseased states. The clinical relevance of this channel cannot be understated. The cardiac INa is the target of the class 1 anti-arrhythmic drugs1, which are nowadays less frequently prescribed because of their well-documented pro-arrhythmic properties2. In addition, since the first description in 1995 by Keating's group3 of mutations in patients suffering from congenital long QT syndrome (LQTS) type 3, several hundred genetic variants in SCN5A, the gene coding for Nav1.5, have been reported and investigated4. Interestingly, many of these genetic variants have been found in patients with diverse cardiac manifestations5 such as congenital LQTS type 3, Brugada syndrome, conduction disorders, and more recently, atrial fibrillation and dilated cardiomyopathy. This impressive list underlines the importance of Nav1.5 in cardiac pathologies and raises the question about possible unknown roles and regulatory mechanisms of this channel in cardiac cells. Recent studies have provided experimental evidence that the function of Nav1.5, among many other described regulatory mechanisms6, is also modulated by the mechanical stretch of the membrane in which it is embedded7, thus suggesting that Nav1.5, like other ion channels, is "mechanosensitive". What does this mean? (SELECT FULL TEXT TO CONTINUE)
- Received May 2, 2012.
- Accepted May 4, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited