Channelopathies and drug discovery in the postgenomic era

Abstract

Ion channels are a diverse group of pore-forming proteins that provide selective pathways for the movement of ions (Na+, K+, Ca2+, Cl−, etc) across the lipid membrane barrier. Aquaporins facilitate water movement across cell membranes in response to osmotic gradients. There is an increasing body of information on the molecular structure and functional roles of ion and water channels in health and disease, linking channel function at the molecular level to organ physiology. Because ion channels play essential roles in all cells, defects in ion channels are associated with a wide variety of pathophysiological conditions and human diseases. Diseases caused by disturbed function of ion channel subunits or regulatory proteins have been defined as “channelopathies”1, 2. In the postgenomic era the rapid progress in the molecular identification of genes for new ion channels and elucidation of their transport properties, physiological functions, and disease relevant mutations has significantly advanced the knowledge of channelopathies and potential new therapies3, 4, 5, 6, 7, 8, 9. For examples, the discovery of aquaporin water channels, a family of integral membrane proteins that selectively transport water, has led to the identification of water channelopathies including autosomal dominant and recessive forms of hereditary nepherogenic diabetes insipidus caused by aquaporin-2 mutations10, congenital cataracts incurred by aquaporin-0 mutations11 and aquired neuronal inflammatory disease neuromyelitis optica in which pathogenic autoantibodies target aquaporin-412. Impaired Cl− transport caused by mutations in genes belonging to distinct Cl− channel families has been found to cause diverse diseases such as cystic fibrosis, myotonia, epilepsy, hyperekplexia, lysosomal storage disease, deafness, renal salt loss, kidney stones, osteopetrosis, and cardiovascular diseases7, 13, 14. In addition, the studies on the role of ion channel regulatory proteins, including the sub-membrane adapter ankyrins and alpha-1 syntrophin, membrane coat protein caveolin-3, signaling platform yotiao, and lamins, have also provided novel insights into understanding of human diseases15.