MOLECULAR-BASIS OF THE DIVERSITY OF CALCIUM CHANNELS IN CARDIOVASCULAR TISSUES

Voltage-dependent calcium (Ca2+) channels control a variety of physiol ogical functions, such as excitation-contraction coupling in cardiac a nd smooth muscle, secretion of hormones and release of neurotransmitte rs. Studies on dissociated or cultured cells enabled us to compare the ir electrophysiological and pharmacological properties and their regul ation in various tissues. Molecular genetics has provided a structural basis with which to observe the functional diversity of Ca2+ channels , which are composed of several subunits (al, a2- delta, beta, gamma). Structure-function experiments, using expression in Xenopus oocytes, were designed to explain the molecular basis underlying this functiona l diversity. Six genes have been identified encoding the pore subunit (al) which determines the basic profile, i.e. the pharmacology of any Ca2+ channel. However, using a reconstitution model, the auxiliary sub units, but mainly beta subunits, for which four genes and several vari ants have been isolated, are able to modify the level of expression an d the properties of a Ca2+ current directed by an al subunit. Our stru cture-function studies are mainly designed to investigate the function al consequences of al-beta interaction on electrophysiological and pha rmacological properties, especially in the case of cardiovascular Ca2 channels. These studies should lead to a better understanding of the molecular basis underlying the differences between cardiac and vascula r Ca2+ channels and also their implication in pathophysiology. Functio nal expression of the various combinations of subunit isoforms and ide ntification of the precise oligomeric structure of voltage-dependent C a2+ channels in specific cell types should help in the development of new therapeutic drugs.