MOLECULAR DIVERSITY OF CALCIUM CHANNELS - FROM GENE TO FUNCTION

Recent studies have revealed the molecular and functional diversity of voltage-gated calcium channels. Electrophysiological and pharmacologi cal experiments on various cell types have provided a way of character izing a Low Voltage Activated (LVA) or ''T-type'', and several High Vo ltage Activated (HVA) calcium channels. LVA Ca2+ channels have fast ki netics and no specific ligands while HVA Ca2+ channels have been ident ified mainly by the use of specific toxins, and named L, N, P and Q. T hey are blocked by dihydropyridines, omega-CgT-GVIA, omega-Aga-IVA and omega-CmT-MVIIC, respectively. Biochemical studies have revealed that skeletal muscle Ca2+ channels are composed of a pore-forming alpha 1 subunit and several associated subunits (alpha 2-delta, beta and gamma ). Several alpha 1 subunits have been cloned from various tissues and are encoded by at least six genes. Their expression in Xenopus oocytes or in mammalian cells induces calcium channel currents, the propertie s of which seem to correspond to the different Ca2+ channels identifie d in various cells. However, it has been suggested that further divers ity may be provided by the addition of auxiliary subunits and particul arly the beta subunits which are thought to be associated to most of t he alpha 1 subunits. beta subunits encoded by at least four genes (bet a 1, beta 2, beta 3, beta 4) expressed in the nervous system and other tissues enhance Ca2+ channel activity and are able to modify both ele ctrophysiological and pharmacological properties. However, a different ial effect on calcium current inactivation has been observed between t he different isoforms (beta 1, beta 2, beta 3) and their splice varian ts (beta 1a, beta 1b) indicating that multiple Ca2+ channel gating may arise from the expression of different subtypes of beta subunits. The implication of Ca2+ channels in pathophysiology has been recently sug gested and the genes coding for alpha 1 or beta subunits are potential candidates in some patho logies. Several autoimmune diseases have als o been suggested to involve Ca2+ channels as the targets for antibodie s. Moreover, the functional diversity of neuronal Ca2+ channel offers new perspectives in the development of drugs for the treatment of neur ologic disorders.