Discovery of novel sodium channel inhibitors: a gene family-based approach

Voltage-gated sodium (Na_V) channels are widely expressed in most electrically excitable cells. They activate in response to membrane depolarisation, and are responsible for rapid influx of Na⁺ ions during the rising phase of an action potential. They also have a major influence on the resting potential of these cells and thus have a key role in regulating their excitability. Na_V channels have been implicated in a number of human disease states. Seven different inherited disorders have been linked to mutations in Na_V genes, including two cardiac, three skeletal muscle and three neuronal syndromes. Despite the fundamental physiological role of Na_V channels it has been possible to develop therapeutically active Na_V inhibitors that have relatively few side effects. However, these Na_V blocking drugs were all discovered empirically, i.e. using traditional pharmacological methods, rather than by specifically targeting Na_V channels, and only subsequently was it uncovered that they inhibited these channels.