[Molecular aspects of the diversity of cardiovascular calcium channels]

Voltage-dependent calcium channels control various physiological functions such as the excitation-contraction coupling, the secretion of hormones or the release of neurotransmitters in the nervous system. Molecular genetics has allowed to provide a structural basis to the functional diversity of calcium channels and to initiate studies to understand the relations between the structure and the function of these excitable proteins. The aim of our research is to compare both the functional and structural properties of calcium channels from various tissues. The studies on dissociated or cultured cells allow to describe their properties, regulation, pharmacology and pathophysiology in native tissues. Structure-functions studies using reconstitution models such as Xenopus oocytes aim to understand the molecular basis underlying their diversity. Calcium channels are composed of several subunits (alpha 1, alpha 2-delta, beta, gamma). Six genes have been identified as coding for the pore subunit (alpha 1) which determines the general profile and in particular the pharmacology of a given calcium channel. However, the auxilliary subunits and mainly beta subunits for which 4 genes and several variants have been isolated, are able to modify the level of expression and the properties of a calcium current directed by an alpha 1 subunit in a reconstitution model. The structure-function studies are now mainly designed to investigate the functional consequences of the interaction alpha 1-beta on the electrophysiological and pharmacological properties. These studies should lead to a better understanding of the molecular basis underlying the diversity between cardiac and vascular calcium channels and also of their respective implication in pathophysiology. The co-expression of several families of calcium channels in a single neuron do not allow properly to investigate the properties and the regulation (by phosphorylation or G proteins) of the neuronal calcium channels which are involved in neurosecretion. The use of reconstitution models will provide a better characterization of neuronal calcium channels and should help to the development of new drugs of therapeutical interest.