Role of the peripheral-type benzodiazepine receptor and the polypeptide diazepam binding inhibitor in steroidogenesis.
Steroidogenesis begins with the metabolism of cholesterol to pregnenolone by the inner mitochondrial membrane cytochrome P450 side-chain cleavage (P450scc) enzyme. The rate of steroid formation, however, depends on the rate of (i) cholesterol transport from intracellular stores to the inner mitochondrial membrane and (ii) loading of P450scc with cholesterol. We demonstrated that a key element in the regulation of cholesterol transport is the mitochondrial peripheral-type benzodiazepine receptor (PBR) and that the presence of the polypeptide diazepam binding inhibitor (DBI) was vital for steroidogenesis. We also showed that DBI, as the endogenous PBR ligand, stimulates cholesterol transport. In addition, DBI directly promotes loading of cholesterol to P450scc. We review herein our studies on the structure, function, topography and hormonal regulation of PBR and DBI in steroidogenic cells. Based on these data we propose a model where the interaction of DBI with PBR, at the outer/inner membrane contact sites, is the signal transducer of hormone-stimulated and constitutive steroidogenesis at the mitochondrial level. Hormone-induced changes in PBR microenvironment/structure regulate the affinity of the receptor. PBR ligand binding to a higher affinity receptor results in increased cholesterol transport. In addition, hormone-induced release (processing?) of a 30,000 Mw DBI-immunoreactive protein from the inner mitochondrial membrane may result to the intramitochondrial production of DBI which directly stimulates loading of P450scc with cholesterol. Thus, in vivo, hormonal activation of these two mechanisms results in efficient cholesterol delivery and utilization and thus high levels of steroid synthesis.
Papadopoulos
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V
Department of Cell Biology, Georgetown University Medical Center, Washington, DC 20007, USA.
Brown
A S
AS
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002352:Carrier Proteins / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D026261:Diazepam Binding Inhibitor; D007985:Leydig Cells / Q000378:metabolism; D008024:Ligands; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D011963:Receptors, GABA-A / Q000502:physiology*; D013256:Steroids / Q000096:biosynthesis*
D002352:Carrier Proteins; D026261:Diazepam Binding Inhibitor; D008024:Ligands; D011963:Receptors, GABA-A; D013256:Steroids; D002784:Cholesterol