Cardiac Sodium Channel Na v 1.5 Mechanosensitivity Is Inhibited by Ranolazine

Abstract

The cardiac action potential is initiated by the depolarizing inward sodium current ( I Na ). The pore-forming subunit of the cardiac sodium channel, Na v 1.5, is the main ion channel that conducts I Na in cardiac cells. Despite the large number of studies investigating Na v 1.5, 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 I Na is the target of the class 1 antiarrhythmic drugs,1 which are nowadays less frequently prescribed because of their well-documented proarrhythmic properties.2 In addition, since the first description in 1995 by Keating's group3 of mutations in patients experiencing congenital long-QT syndrome type 3, several hundred genetic variants in SCN5A , the gene coding for Na v 1.5, have been reported and investigated.4 Interestingly, many of these genetic variants have been found in patients with diverse cardiac manifestations,5 such as congenital long QT syndrome type 3, Brugada syndrome, conduction disorders, and more recently, atrial fibrillation and dilated cardiomyopathy. This impressive list underlines the importance of Na v 1.5 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 Na v 1.5, among many other described regulatory mechanisms,6 is also modulated by the mechanical stretch of the membrane in which it is embedded,7 thus suggesting that Na v 1.5, like other ion channels, is mechanosensitive. What does this mean? Mechanosensitivity of an ion channel is characterized by modulation of its intrinsic biophysical properties such as conductance, gating, or voltage-dependence of transition between the different states of the channel by the mechanical stretch of the cell membrane …