Molecular diversity of structure and function of the voltage-gated Na+ channels

A variety of different isoforms of voltage-sensitive Na+ channels have now been identified. 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 categories on the basis of their amino acid sequence, Na(V)1 isoforms currently comprising nine highly homologous clones and Na-X that possesses structure diverging from Na(V)1, especially in several critical functional motifs. Although the functional role of Na(V)1 isoforms is primarily to form an action potential upstroke in excitable cells, recent biophysical studies indicate that some of the Na(V)1 isoforms can also influence subthreshold electrical activity through persistent or resurgent Na+ currents. Na(V)1.8 and Na(V)1.9 contain an amino acid sequence common to tetrodotoxin resistant Na+ channels and are localized in peripheral nociceptors. Recent patch-clamp experiments on dorsal root ganglion neurons from Na(V)1.8-knock-out mice unveiled an additional tetrodotoxin-resistant Na+ current. The demonstration of its dependence on Na(V)1.9 provides evidence for a specialized role of Na(V)1.9, together with Na(V)1.8, in pain sensation. Although Na-X has not been successfully expressed in an exogenous system, recent investigations using relevant native tissues combined with gene-targeting have disclosed their unique "concentration"-sensitive but not voltage-sensitive roles. In this context, these emerging views of novel functions mediated by different types of Na+ channels are reviewed, to give a perspective for future research on the expanding family of Na+ channel clones.