Molecular Diversity of Structure and Function of the Voltage-Gated Na+ Channels

Abstract

ABSTRACT-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, NaV1 isoforms currently comprising nine highly homologous clones and NaX 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 NaV1.8, in pain sensation. Although NaX 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.

Voltage-Dependent Enhancement of Electrical Coupling by a Subthreshold Sodium Current

“…Although persistent Na ϩ currents represent a small (ϳ1%) noninactivating fraction of the total Na ϩ current, they have a significant functional impact because they are activated ϳ10 mV negative to the transient Na ϩ current, where few voltage-gated channels are activated and neuron input resistance is high (Crill, 1996). As a result of this property, these subthreshold Na ϩ currents play essential cellular roles in amplifying dendritric synaptic potentials, regulating repetitive firing, and producing depolarizing responses (for review, see Crill, 1996;Ogata and Ohishi, 2002). Persistent Na ϩ currents have also been reported to be present in sensory axons (Kocsis and Waxman, 1983;Bowe et al 1985;Honmou et al, 1994).…”

Sodium Channels in Transient Retinal Bipolar Cells Enhance Visual Responses in Ganglion Cells

“…The molecular basis of transient and persistent sodium currents is unclear. Molecular analysis has not identified two separate subtypes of sodium channels that correspond to the different current kinetics observed (Ogata and Ohishi, 2002). It was proposed that two different types of sodium currents are generated by a uniform population of channels that can switch between different gating modes (Alzheimer et al, 1993).…”

Jingzhaotoxin-III, a Novel Spider Toxin Inhibiting Activation of Voltage-gated Sodium Channel in Rat Cardiac Myocytes

“…Most of them can express in dorsal root ganglion (DRG) neurons, except for Na v 1.4 in skeletal muscles and Na v 1.5 in cardiac myocytes (4). These subtypes have been highly conserved during evolution (5,6).…”