Cytochrome P-450 may link intracellular Ca2+ stores with plasma membrane Ca2+ influx

Abstract

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.

Farnesylcysteine analogues inhibit store-regulated Ca2+ entry in human platelets: evidence for involvement of small GTP-binding proteins and actin cytoskeleton

“…Many different messenger molecules have been proposed to be involved in store-regulated Ca# + entry (SRCE) : cGMP [6], cytochrome P450 metabolites [7], a tyrosine kinase-dependent step [8,9], release of a Ca# + influx factor from depleted stores [10] or a Ca# + \calmodulin kinase-dependent step [11]. Fasolato et al [12] have presented evidence for the involvement of small GTPbinding proteins in SRCE in RBL cells.…”

Wortmannin inhibits store‐mediated calcium entry and protein tyrosine phosphorylation in human platelets

“…In many cell types including human platelets, depletion of intracellular Ca 2+ stores evokes influx of Ca 2+ across the plasma membrane [1][2][3]. However, the mechanism of this store-mediated (or 'capacitative') Ca 2+ entry [4] remains uncertain.…”

The Role of Mitochondria for Ca2+ Refilling of the Endoplasmic Reticulum

“…Refs. [7][8][9][10][11] and its/their molecular nature are still under debate (12)(13)(14), recent investigations point to a fundamental role of mitochondria in the maintenance (15)(16)(17)(18)(19) and modulation (20) of the CCE in many cell types. Notably, the intriguing aptitude of mitochondria to effectively impound subplasmalemmal Ca 2ϩ (i.e.…”