Molecular and cellular aspects of calcium channel antagonism

Calcium fluxes play a key role in controlling many physiologic processes and responses in the body. The past few years have witnessed major advances in understanding of L-type calcium channels and their blockade with calcium channel antagonists. The L-type calcium channels comprise 5 subunits termed alpha 1, alpha 2, beta, gamma, and delta. Elucidation of the mechanisms of action of the calcium channel antagonists has been advanced by cloning and genetic manipulation of these subunits. The alpha 1 subunit appears to be responsible for channel opening and voltage dependency, and it contains receptors for calcium channel antagonists; these geographically distinct receptors correspond to each of the 3 different chemical classes of antagonists, exemplified by diltiazem, nifedipine, and verapamil. Diltiazem appears to have an inhibitory effect on mitochondrial sodium-calcium exchange that is unique among calcium channel antagonists. Preliminary data suggest that a diltiazem-specific receptor also exists in the endothelium. It appears, therefore, that despite advances in the understanding of L-type calcium channels, much remains to be learned about other possible receptors for the calcium channel antagonists.