Identification of des-(Gly-Ile)-endozepine as an effector of corticotropin-dependent adrenal steroidogenesis: stimulation of cholesterol delivery is mediated by the peripheral benzodiazepine receptor.

Abstract

Delivery ofcholesterol to inner mitochondrial membranes is rate-limiting for steroidogenesis in the zona fasciculata of adrenal cortex. A protein that stimulates this process was isolated to homogeneity from bovine adrenal tissue. This protein's primary structure has been determined in its entirety by a combination of automated Edman microsequencing, fast-atom bombardment mass spectrometry (FAB-MS). The sequence was identical to that previously reported for bovine brain endozepine, except that it lacks the last two residues, -Gly-Ile, at the C terminus. To our knowledge, isolation of an endozepine-related protein from a tissue other than brain has not been reported previously. Endozepine competes with benzodiazepines for saturable binding sites in synaptosomes and in mitochondria of specific peripheral tissues. Previous reports have localized the adrenal benzodiazepine receptor to the outer mitochondrial membrane. In this report, we show that the prototypic benzoiazepine, diazepam, effects a stimulation of adrenal mitochondrial cholesterol delivery similar to that observed for endozepine. The effective diazepam concentration was consistent with that previously shown to displace a high-affinity ligand of the mitochondrial benzodiazepine receptor. The action of diazepam in adrenal mitochondria suggests that the mediation of corticotropininduced steroidogenesis may be the physiological function of the peripheral-type benzodiazepine receptor. These studies provide new insights into the previously unknown function of peripheral benzodiazepine receptors and should allow new investigations into the stimulation of steroidogenesis by endozepines and benzodiazepines in the brain and in certain peripheral tissues.

Gene expression profiling of bovine preovulatory follicles: gonadotropin surge and prostanoid-dependent up-regulation of genes potentially linked to the ovulatory process

“…As the endogenous ligand for benzodiazepine (BZD) receptors (BZR), DBI can displace BZD from BZR. DBI can stimulate in vivo steroidogenesis via binding to peripheral BZR resulting in increased pregnenolone synthesis (Besman et al 1989, Papadopoulos et al 1991. DBI expression in the rat ovary has been reported previously (Bovolin et al 1990, Toranzo et al 1994).…”

“…ADAM10 belongs to the ADAM family of transmembrane proteinases linked to processing of EGF family ligands (Blobel 2005) that mediate LH action (cumulus expansion, oocyte maturation, ovulation) during the periovulatory period in mice (Park et al 2004, Conti et al 2006. DBI is present in the rat ovary (Bovolin et al 1990, Toranzo et al 1994 and is a known stimulator of steroidogenesis/pregnenolone biosynthesis (Besman et al 1989, Papadopoulos et al 1991. CD36 is a multifunctional scavenger receptor that binds known autocrine growth factors that can regulate cell growth, adhesion, and angiogenesis (Febbraio et al 2001).…”

Diazepam-binding inhibitor-derived peptides induce intracellular calcium changes and modulate human neutrophil function

“…In view of the fact that DBI is released from nerve terminals and its fragments can be found in liquor and peripheral blood [33], such peptides may represent novel neuroendocrine mediators linking the central nervous system to the immune system. Moreover, inasmuch as DBI or a protein with an identical amino acid sequence, previously named acyl-CoA binding protein, is also widely distributed in many peripheral organs such as gut and endocrine cells of the pancreatic islets [5,34], liver, kidney [35], adrenals [36], adipose tissue, heart, muscles, and mammary gland [37] of different species, and in circulating mononuclear cells [38], in red blood cells [39], and even in neoplastic cell lines [40], it cannot be excluded that high concentrations of DBI and/or of its processing products may occur locally as the result of leakage from damaged cells during tissue injury. DBI-derived peptides may thus also add to the multiple agents constituting the local microenvironment in inflamed tissues.…”

The adolescent brain and age-related behavioral manifestations

“…Adrenal activation by the sympathetic nervous system may prove to be critical [151]. One possible regulator of the adrenarchespecific stimulation of adrenal androgen production may be the polypeptide diazepam binding inhibitor (DBI), a presumed endogenous GABA A modulator that has been shown to facilitate ACTH-stimulated steroidogenesis in the adrenals of laboratory animals [43,53]. The ontogeny of DBI and its potential relationship to adrenarche in humans, however, have yet to be explored.…”