Sodium channel traffic on the cardiac microtubule highway

Abstract

Voltage-gated sodium channels are responsible for excitable cell action potential initiation. In cardiomyocytes, SCN5A -encoded Nav1.5 is the primary voltage-gated sodium channel α subunit, although other Nav channel α subunits may secondarily modulate specific I Na properties. In addition to the pore-forming Nav1.5 α subunits, four accessory Nav β subunits (β1–β4) are expressed in the human heart. These β subunits have been hypothesized to affect anterograde membrane trafficking of Nav channel α subunits. The critical role of Nav1.5 for normal cardiac function is clearly demonstrated by cardiac defects in mice lacking Nav1.51 as well as by severe ventricular, atrial, and sinoatrial node arrhythmia phenotypes in patients harbouring gain- or loss-of-function mutations in SCN5A or in Nav channel β subunits (β1–β4).2 Over the past decade, work from a number of laboratories has defined the fundamental biophysical properties of Nav1.5 both in heterologous cells and in vivo .3 Additionally, high-resolution analyses of key Nav1.5 structural domains have provided exciting new insights into the mechanisms underlying Nav1.5 regulation.4 However, only recently has the field focused on investigating the cellular pathways required for the local expression and regulation … *Corresponding author. Tel: +1 319 335 9691; fax +1 319 353 5552, Email: peter-mohler{at}uiowa.edu