Cytochrome P450 may regulate plasma membrane Ca2+ permeability according to the filling state of the intracellular Ca2+ stores.
The filling state of the intracellular Ca2+ stores of rat thymocytes regulates plasma membrane permeability to Mn2+, used here as a Ca2+ surrogate for plasma membrane Ca2+ channels. Emptying of the Ca2+ stores accelerated Mn2+ entry about 10-fold, and refilling with Ca2+ restored low Mn2+ permeability. The acceleration of Mn2+ entry observed in cells with empty intracellular Ca2+ stores was prevented by cytochrome P450 inhibitors. Imidazole antimycotics, especially econazole and miconazole, were the most potent inhibitors (IC50 approximately equal to 10(-6) M). The inhibitor sensitivity profile was similar to IA-type cytochrome P450. Calmodulin antagonists increased the plasma membrane permeability to Mn2+ in cells with filled Ca2+ stores, and this effect was also blocked by imidazole antimycotics. On this basis, we propose a model in which activation of a cytochrome P450, situated at the Ca2+ stores, opens a plasma membrane Ca2+ pathway. This activity would be inhibited by Ca2+ inside the stores by a calmodulin-dependent mechanism.
Alvarez
J
J
Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Spain.
Montero
M
M
Garcia-Sancho
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers; D006706:Homeostasis; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D008345:Manganese / Q000378:metabolism; D008954:Models, Biological; D051381:Rats; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism*; D014268:Trifluoperazine / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007093:Imidazoles; D014268:Trifluoperazine; D008345:Manganese; D003577:Cytochrome P-450 Enzyme System; D002118:Calcium