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

Abstract

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 ≌ 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.; Montero, M.; Garcia-Sancho, J. Cytochrome P450 may regulate plasma membrane Ca²⁺ permeability according to the filling state of the intracellular Ca²⁺ stores. FASEB J. 6: 786-792; 1992.