Calcium channel diversity in the cardiovascular system

The flux of calcium ions (Ca2+) into the cytosol, where they serve as intracellular messengers, is regulated by two distinct families of Ca2+ channel proteins. These are the intracellular Ca2+ release channels, which allow Ca2+ to enter the cytosol from intracellular stores, and the plasm membrane Ca2+ channels, which control Ca2+ entry from the extracellular space. Each of these two families of channel proteins contains several subgroups. The intracellular channels include the large Ca2+ channels (“ryanodine receptors”) that participate in cardiac and skeletal muscle excitation-contraction coupling, and smaller inositol trisphosphate (InsP3)—activated Ca2+ channels. The latter serve several functions, including the pharmacomechanical coupling that activates smooth muscle contraction, and possibly regulation of diastolic tone in the heart. The InsP3-activated Ca2+ channels may also participate in signal transduction systems that regulate cell growth. The family of plasm membrane Ca2+ channels includes L-type channels, which respond to membrane depolarization by generating signal that opens the intracellular Ca2+ release channels. Calcium ion entry through L-type Ca2+ channels in the sinoatrial (SA) node contributes to pacemaker activity, whereas L-type Ca2+ channels in the atrioventricular (AV) node are essential for AV conduction. The T-type Ca2+ channels, another member of the family of plasm membrane Ca2+ channels, participate in pharmacomechanical coupling in smooth muscle. Opening of these channels in response to membrane depolarization participates in S node pacemaker currents, but their role in the working cells of the atri and ventricle is less clear. Like the InsP3-activated intracellular Ca2+ release channels, T-type plasm membrane channels may regulate cell growth. Because most of the familiar Ca2+ channel blocking agents currently used in cardiology, such as nifedipine, verapamil and diltiazem, are selective for L-type Ca2+ channels, the recent development of drugs that selectively block T-type Ca2+ channels offers promise of new approaches to cardiovascular therapy.