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 plasma membrane Ca2+ channels, which control Ca2+ entry from the e xtracellular space. Each of these two families of channel proteins con tains several subgroups. The intracellular channels include the large Ca2+ channels (''ryanodine receptors'') that participate in cardiac an d skeletal muscle excitation-contraction coupling, and smaller inosito l trisphosphate (InsP(3))-activated Ca2+ channels. The latter serve se veral functions, including the pharmacomechanical coupling that activa tes smooth muscle contraction, and possibly regulation of diastolic to ne in the heart. The InsP(3)-activated Ca2+ channels may also particip ate in signal transduction systems that regulate cell growth. The fami ly of plasma membrane Ca2+ channels includes L type channels, which re spond to membrane depolarization by generating a signal that opens the intracellular Ca2+ release channels. Calcium ion entry through L-type Ca2+ channels in the sinoatrial (SA) node contributes to pacemaker ac tivity, whereas L-type Ca2+ channels in the atrioventricular (AV) node are essential for AV conduction. The T-type Ca2+ channels, another me mber of the family of plasma membrane Ca2+ channels, participate in ph armacomechanical coupling in smooth muscle. Opening of these channels in response to membrane depolarization participates in SA node pacemak er currents, but their role in the working cells of the atria and vent ricle is less clear. Like the InsP(3)-activated intracellular Ca2+ rel ease channels, T type plasma membrane channels may regulate cell growt h. 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 th at selectively block T-type Ca2+ channels offers promise of new approa ches to cardiovascular therapy.