Functional roles of tetrodotoxin-insensitive sodium channels in nociception

Abstract

A variety of different isoforms of voltage-gated Na⁺ channels have now been cloned. The recent three-dimensional analysis of Na⁺ channels has unveiled a unique and unexpected structure of the Na⁺ channel protein. Na⁺ channels can be classified into two major categories, Na_v1 isoforms currently comprising nine highly homologous clones, and Na_x that has structure diverging from Na_v1. Although Na_x has not been successfully expressed in an exogenous system, recent studies using gene-targeting have unveiled their unique “concentration”-sensitive but not voltage-sensitive role. The functional role of Na_v1 isoforms is primarily to carry action potential generation in excitable cells. However, some of the Na_v1 isoforms can also influence subthreshold electrical activity through a persistent type of Na⁺ current. Na_v1.8 and Na_v1.9 contain an amino acid sequence common to tetrodotoxin (TTX)-resistant Na⁺ channels and are localized in small primary sensory neurons that mediate pain sensation. Our patch-clamp recordings from DRG neurons of Na_v1.8-null mutant mice disclosed a novel TTX-insensitive Na⁺ current. The demonstration of its dependence on Na_v1.9 transcripts provided evidence for a specialized role of Na_v1.9, together with Na_v1.8, in pain sensation. In this article, these emerging views of novel functions mediated by multiple types of Na⁺ channels are summarized, to give a perspective for the expanding Na⁺ channel mutigene family.