Molecular basis of the diversity of calcium channels in cardiovascular tissues.
Voltage-dependent calcium (Ca2+) channels control a variety of physiological functions, such as excitation-contraction coupling in cardiac and smooth muscle. secretion of hormones and release of neurotransmitters. Studies on dissociated or cultured cells enabled us to compare their electrophysiological and pharmacological properties and their regulation 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 (alpha 1, alpha 2-delta, beta, gamma). Structure-function experiments, using expression in Xenopus oocytes, were designed to explain the molecular basis underlying this functional diversity. Six genes have been identified encoding the pore subunit (alpha 1) which determines the basic profile, i.e. the pharmacology of any Ca2+ channel. However, using a reconstitution model, the auxiliary subunits, but mainly beta subunits, for which four genes and several variants have been isolated, are able to modify the level of expression and the properties of a Ca2+ current directed by an alpha 1 subunit. Our structure-function studies are mainly designed to investigate the functional consequences of alpha 1-beta interaction on electrophysiological and pharmacological 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 vascular Ca2+ channels and also their implication in pathophysiology. Functional expression of the various combinations of subunit isoforms and identification of the precise oligomeric structure of voltage-dependent Ca2+ channels in specific cell types should help in the development of new therapeutic drugs.
Nargeot
J
J
Centre des Recherches de Biochimie Macromoléculaire, Montpellier, France.
Lory
P
P
Richard
S
S
D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D003001:Cloning, Molecular; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D006801:Humans; D008564:Membrane Potentials; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques
D015220:Calcium Channels