Cytochrome P450 may regulate plasma membrane Ca 2+ permeability according to the filling state of the intracellular Ca 2+ stores

The filling state of the intracellular Ca 2+ stores of rat thymocytes regulates plasma membrane permeability to Mn 2+ , used here as a Ca 2+ surrogate for plasma membrane Ca 2+ channels. Emptying of the Ca 2+ stores accelerated Mn 2+ entry about 10‐fold, and refilling with Ca 2+ restored low Mn 2+ permeability. The acceleration of Mn 2+ entry observed in cells with empty intracellular Ca 2+ stores was prevented by cytochrome P450 inhibitors. Imidazole antimycotics, especially econazole and miconazole, were the most potent inhibitors (IC 50 ≌ 10 –6 m ). The inhibitor sensitivity profile was similar to IA‐type cytochrome P450. Calmodulin antagonists increased the plasma membrane permeability to Mn 2+ in cells with filled Ca 2+ 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 Ca 2+ stores, opens a plasma membrane Ca 2+ pathway. This activity would be inhibited by Ca 2+ inside the stores by a calmodulin‐dependent mechanism.—Alvarez, J.; Montero, M.; Garcia‐Sancho, J. Cytochrome P450 may regulate plasma membrane Ca 2+ permeability according to the filling state of the intracellular Ca 2+ stores. FASEB J. 6: 786‐792; 1992.