MOLECULAR DETERMINANTS OF DRUG-BINDING AND ACTION ON L-TYPE CALCIUM CHANNELS

The crucial role of L-type Ca2+ channels in the initiation of cardiac and smooth muscle contraction has made them major therapeutic targets for the treatment of cardiovascular disease. L-type channels share a c ommon pharmacological profile, including high-affinity voltage- and fr equency-dependent block by the phenylalkylamines, the benz(othi)azepin es, and the dihydropyridines. These drugs are thought to bind to three separate receptor sites on L-type Ca2+ channels that are allosterical ly linked. Results from different experimental approaches implicate th e IIIS5, IIIS6, and IVS6 transmembrane segments of the alpha(1) subuni ts of L-type Ca2+ channels in binding of all three classes of drugs. S ite-directed mutagenesis has identified single amino acid residues wit hin the IIIS5, IIIS6, and IVS6 transmembrane segments that are require d for high-affinity binding of phenylalkylamines and/or dihydropyridin es, providing further support for identification of these transmembran e segments as critical elements of the receptor sites for these two cl asses of drugs. The close proximity of the receptor sites for phenylal kylamines, benz(othi)azepines, and dihydropyridines raises the possibi lity that individual amino acid residues may be required for high-affi nity binding of more than one of these ligands. Therefore, we suggest that phenylalkylamines and dihydropyridines bind to different faces of the IIIS6 and IVS6 transmembrane segments and, in some cases, bind to opposite sides of the side chains of the same amino acid residues. Th e results support the domain interface model for binding and channel m odulation by these three classes of drugs.