Voltage-gated sodium channels in excitable cells as drug targets

Excitable cells — including neurons, muscle cells and cardiac myocytes — are unique in expressing high densities of voltage-gated sodium (Na_V) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of ‘the’ sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (Na_V1.1–Na_V1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these Na_V subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.