Cytochrome P-450 may link intracellular Ca2+ stores with plasma membrane Ca2+ influx.
We have studied the mechanism of the regulation of plasma membrane Ca2+ permeability by the degree of filling of the intracellular Ca2+ stores. Using Mn2+ as a Ca2+ surrogate for plasma membrane Ca2+ channels, we found that Mn2+ uptake by rat thymocytes is inversely related to the degree of filling of the intracellular Ca2+ stores. This store-dependent plasma membrane permeability is inhibited by oxygen scavenging, CO, imidazole antimycotics and other cytochrome P-450 inhibitors. The pattern of inhibition is similar to that reported previously for the inhibition of microsomal cytochrome P-450-mediated aryl hydrocarbon hydroxylase activity of lymphocytes. Several calmodulin antagonists, both phenothiazinic (trifluoperazine, fluphenazine and chlorpromazine) and dibenzodiazepinic (clozapine), accelerate Mn2+ uptake by cells with Ca2(+)-filled stores, and this effect is prevented by imidazole antimycotics. Our results suggest that cytochrome P-450 may be the link between the stores and the plasma membrane Ca2+ pathway. We propose a model in which this cytochrome, sited at the stores, stimulates plasma membrane Ca2+ influx. This stimulatory effect is, in turn, prevented by the presence of Ca2+ inside the stores, possibly via a calmodulin-dependent mechanism.
Alvarez
J
J
Departamento de Bioquímica, Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Spain.
Montero
M
M
García-Sancho
J
J
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002286:Carcinoma, Ehrlich Tumor / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005476:Fluphenazine / Q000494:pharmacology; D016257:Fura-2; D006801:Humans; D066298:In Vitro Techniques; D015759:Ionomycin / Q000494:pharmacology; D007700:Kinetics; D008345:Manganese / Q000378:metabolism; D051379:Mice; D051381:Rats; D013950:Thymus Gland / Q000378:metabolism; D014268:Trifluoperazine / Q000494:pharmacology
D014268:Trifluoperazine; D008345:Manganese; D015759:Ionomycin; D003577:Cytochrome P-450 Enzyme System; D005476:Fluphenazine; D002118:Calcium; D016257:Fura-2; D002746:Chlorpromazine