A New Cardiac Channelopathy: From Clinical Phenotypes to Molecular Mechanisms Associated With Nav1.5 Gating Pores

Abstract

Voltage gated sodium channels (Na_V) are broadly expressed in the human body. They are responsible for the initiation of action potentials in excitable cells. They also underlie several physiological processes such as cognitive, sensitive, motor, and cardiac functions. The Na_V1.5 channel is the main Na_V expressed in the heart. A dysfunction of this channel is usually associated with the development of pure electrical disorders such as long QT syndrome, Brugada syndrome, sinus node dysfunction, atrial fibrillation, and cardiac conduction disorders. However, mutations of Na_v1.5 have recently been linked to the development of an atypical clinical entity combining complex arrhythmias and dilated cardiomyopathy. Although several Na_v1.5 mutations have been linked to dilated cardiomyopathy phenotypes, their pathogenic mechanisms remain to be elucidated. The gating pore may constitute a common biophysical defect for all Na_V1.5 mutations located in the channel's VSDs. The creation of such a gating pore may disrupt the ionic homeostasis of cardiomyocytes, affecting electrical signals, cell morphology, and cardiac myocyte function. The main objective of this article is to review the concept of gating pores and their role in structural heart diseases and to discuss potential pharmacological treatments.

Keywords: Nav1.5; SCN5A; cardiac arrhythmias; cardiomyocytes; dilated cardiomyopathy; gating pore current.

Figure 1

(A) Structure of Na_V1.5 voltage-gated sodium channel illustrating the four homologous domains of the channel. The VSD formed by the S1-S4 segments of each domain are represented by light gray segments. The dark gray segments represent the pore domain of the channel. Symbols indicate the locations of the Na_V1.5 VSD mutations associated with the development of cardiac arrhythmias and DCM. Red symbols mutation reported to cause gain of function, green symbols loss of function and blue symbols no effect or no known effect on the channel. (B) Schematic representation of Na_V1.5 sodium channel illustrating the central pore and the presence of a gating pore in one of the VSDs.