“Calcium antagonists”: A class of drugs with a bright future. Part I. Cellular calcium homeostasis and calcium as a coupling messenger

Abstract

The aim of this series of minireviews is to present material from multidisciplinary sources to facilitate the understanding of the pharmacology and the ample clinical potential of a class of drugs that were originally designated as “calcium antagonists” and more recently have been referred to as “calcium entry blockers”, “calcium slow channel blockers” or “calcium modulators”. In this first report our attention will be focussed on the pivotal role of Ca ++ as a messenger linking stimuli of extracellular origin to the intracellular environment. Eucaryotic cells have a number of powerful means to control their cytosolic Ca ++ concentration. Firstly, in a cell at rest the cellular membrane is relatively impermeable to passive Ca ++ movements. This property of the plasmalemma prevents the high free Ca ++ concentration (∼1 mM) of the extracellular compartment from invading the cytosol (∼0.1 μM). However, extracellular Ca ++ can reach the cytosol through the Na +/Ca ++ exchange mechanism and the plasmalemma possesses special Ca ++ channels the conductance of which is controlled by gates that are opened by critical changes in cellular polarization (voltage-operated channel: VOC) or by receptor activation (receptor-operated channel: ROC). The Ca ++ entering via VOC or ROC can subsequently trigger the liberation of Ca ++ from the sarcoplasmic reticulum or from calcium stores located in the inner side of the plasmalemma. The intracellular message generated by external stimuli is transferred to the response mechanism by several cytosolic proteins that require Ca ++ as activator. Finally, the termination of the response is the result of a reduction in the cytosolic Ca ++ concentration that is accomplished by the Na +/Ca ++ exchange mechanism or by energy-dependent pumps which extrude Ca ++ from the cell or store it in subcellular organelles. Therefore, any of the numerous steps of the excitation-response coupling which emply Ca ++ as a messenger or as a protein activator can be the site of action of a pharmacological agent. In the follow-up minireview, some methods to determine the basic pharmacological profile of compounds interfering with cellular Ca ++-dependent functions will be described.