Voltage-gated sodium channels and pain recent advances

© 2003 by Marcel Dekker, Inc. Voltage-gated sodium (Na+) channels (VGSCs) are complex, transmembrane proteins that have a role in governing electrical activity in excitable tissues. The Na+ channel is activated in response to depolarization of the cell membrane that causes a voltage-dependent conformational change in the channel from a resting, closed conformation to an active conformation, the result of which increases the membrane permeability to Na+ ions (1-3). VGSCs comprise a multisubunit complex consisting of a large (230-to 270-kDa), highly glycosylated a-subunit and one or two smaller accessory β-subunits (β1 and β2)' Most attention has been directed toward the a-subunit, and recent molecular studies have extended the a-subunit gene family to ten separate members that have been characterized in terms of their electrophysiological properties and tissue distribution profile (Figs. I and 2) (418). Based on the sensitivity to a toxin derived from puffer fish, tetrodotoxin (TTX), Na+ currents can be subdivided as either being TTX-sensitive (TTXs) or TTX-resistant (TTXr) (19-24). The four brain-type Na+ channels (brain I, II, ill, and VI) which are predominantly found in the central nervous system (CNS) are inhibited by low nanomolar concentrations of TTX (5,7,11,13). PN-I, which is found in neuroendocrine tissues and in sensory nerves, is also TTXsensitive (12,16), as is the skeletal muscle channel a-subunit (17). By contrast, there are three channels that are inhibited by only micromolar concentrations of TTX, the major cardiac channel hl/SKM2 (10) and two channels, SNS and SNS2 which are expressed only in sensory neurones (4,14,15,18).