The role of sodium channels in disease

Native sodium channels exist as polypeptide multimers of an alpha-subunit (260 kDa) and subsidiary and smaller beta-subunits, which are divided into at least three subtypes--beta(1), beta(2) and beta(3). The alpha-subunits are structurally diverse, arising from multiple sodium channel genes and alternative splicing events. Recent progress has led to a good understanding of the molecular structure of sodium channels, how they work and the significance of their expression in particular cell types. This, coupled with experimental studies linking particular isoforms with particular disease states and the discovery of distinct human sodium channelopathies (specific mutations in specific isoforms that cause a variety of diseases, including paralysis, long QT syndrome and epilepsy), is beginning to reveal how particular sodium channel subtypes underlie specific pathologies. All this provides great potential for the development of new therapies. The first generation of sodium channel blockers has led to a broad-spectrum anticonvulsant that is now widely used (lamotrigine) and an impressive neuroprotective agent that is in clinical trials for stroke (sipatrigine). The development of the next generation of sodium channel blockers will be greatly facilitated by elaboration of the pharmacology of the various isoforms, which itself is dependent upon the existence of reliable, rapid and high-throughput assays for sodium channel activity.