Molecular biology of calcium channels in the cardiovascular system

Calcium ions are key intracellular messengers in the cardiovascular system. Calcium homeostasis is regulated by an extracellular cycle, which controls the entry and removal of calcium between the cytosol and extracellular space, and an intracellular cycle, which controls calcium fluxes between the cytosol and intracellular stores in the sarcoplasmic reticulum. Several protein families mediate these calcium fluxes including those that (1) regulate the entry of calcium into the cytosol; (2) recognize calcium within the cytosol; and (3) remove calcium from the cytosol. Intracellular calcium binding proteins (the "E-F hand" proteins) recognize the appearance of calcium in the cytosol; in the heart and vascular smooth muscle, these proteins initiate excitation-contraction coupling. Calcium efflux occurs via adenosine triphosphate (ATP)-dependent calcium pumps and sodium-calcium exchangers, while two families of channels--intracellular release calcium channels and plasma membrane calcium channels--regulate calcium entry into the cytosol. The plasma membrane calcium channels, which include the L- and T-type channels, are of the greatest clinical interest because they are targets for pharmacologic therapy. T-type calcium channels, which activate contraction in vascular smooth muscle but have little or no role in cardiac excitation-contraction coupling, appear to be involved in signal transduction pathways that promote cell growth and proliferation. Calcium channel blockers that selectively block T-type calcium channels, therefore, offer a novel approach to cardiovascular drug therapy.