New Perspectives on the Structure and Function of the Na+ Channel Multigene Family

Abstract

Recent studies on the voltage-gated Na+ channel (VGSC) have revealed several excellent discoveries regarding its structure and function. This article summarizes recent findings on VGSCs, and presents our views on the subject. Based on the multi-pore 3D model of the VGSC, we propose a ”twist-sprinkler“ model: (i) twisting and untwisting of the central cavity corresponds to the closed and open states of the channel, and (ii) cytoplasmic outlet pores sprinkle Na+ ions laterally over the inner surface of the plasma membrane to effect a rapid depolarization. VGSCs can be classified into two major categories. Category-I isoforms currently comprise nine highly homologous clones (Nav1.1- Nav1.9), most of which have been functionally expressed. In contrast, the category-II isoform consists of one clone (Nax), which has not been successfully expressed in an exogenous system. It is considerably different from the category-I isoforms, especially in the S4 segment, and shows little voltage dependence. The main function of the category-I isoforms is to form an action potential upstroke. However, NaV1.6 can also influence subthreshold electrical activity in neurons through the ”persistent“ and ”resurgent“ Na+ currents, indicating that the VGSC itself can modulate overall neuronal firing behavior. NaV1.8 and NaV1.9 are preferentially expressed in peripheral nociceptive neurons and contain a structure common to tetrodotoxin (TTX)-resistant Na+ channels. Both Nav1.8 and Nav1.9 play a pivotal role in pain sensation. The category-II isoform Nax (x = unknown function) is a ”concentration-sensitive“ but not ”voltage-sensitive“ Na+ channel. It is involved in regulation of salt intake behavior by sensing an increase in [Na+]o, and it should be renamed as Nac (c = concentration). Keywords: Na Channel, Multigene Family, INFLAMMATORY PAIN