Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A recognition site for benzodiazepines structurally different from that linked to various gamma-aminobutyric acid A (GABAA) receptor subtypes is located on the outer mitochondrial membranes of steroidogenic cells. This protein has been signified to be important in the regulation of steroid biosynthesis. Because of its location it is designated herein as the mitochondrial benzodiazepine receptor (MBR). A putative endogenous ligand for MBR is the peptide diazepam binding inhibitor (DBI), previously shown to displace drugs from MBR and to be expressed and stored in steroidogenic cells rich in MBR. The two model systems used to study steroidogenic regulation by DBI were the Y-1 adrenocortical and MA-10 Leydig cell lines previously shown to be applicable in studies of mitochondrial steroidogenesis. Both cell lines contain DBI as well as DBI processing products, including the DBI fragments that on reverse phase HPLC coelute with the naturally occurring triakontatetraneuropeptide [TTN; DBI-(17-50)] and octadecaneuropeptide [DBI-(33-50)]. When DBI purified from rat brain was added to mitochondria prepared from Y-1 and MA-10 cell lines, it increased the rates of pregnenolone formation in a dose-related manner. In both cell lines, maximal stimulation (3-fold) of mitochondrial steroidogenesis was obtained with 0.33 microM DBI, with an EC50 of approximately 0.1 microM. However, DBI concentrations higher than 1 microM caused a smaller increase in pregnenolone formation. Flunitrazepam, a benzodiazepine that binds with high nanomolar affinity to MBR, was recently shown to act as an antagonist of ACTH and LH/hCG-induced steroidogenesis and was found in the present studies to inhibit DBI-stimulated mitochondrial steroidogenesis. During the incubation with mitochondria, DBI was partially processed to different peptide fragments, including octadecaneuropeptide and TTN. To determine whether DBI processing products influence mitochondrial steroid biosynthesis, several DBI fragments and other peptides structurally unrelated to DBI were tested. Among these, only TTN stimulated mitochondrial steroid synthesis in a dose-dependent manner similar to DBI.
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PMID:Diazepam binding inhibitor and its processing products stimulate mitochondrial steroid biosynthesis via an interaction with mitochondrial benzodiazepine receptors. 165 52

The distribution of diazepam binding inhibitor (DBI), a multi-function peptide which has recently been discovered, was studied in the rat and human central nervous system and in peripheral organs of the rat by light and electron microscopical immunohistochemistry. In the central nervous system, DBI-LI was localized in many glial cells and glial tumors, and in some neurons. In the periphery, DBI-LI was found in many tissues but it was expressed selectively in specialized cell types. Intense DBI-LI was observed in some endocrine, steroid-producing cells such as glomerular cells of the adrenal gland and Leydig cells of the of the testis. Different types of epithelial cells, for instance distal convoluted tabular cells of the kidney and mucosal cells of the small intestine, displayed moderate DBI-LI. Some supporting cells, such as Schwann cells and Sertoli cells, were also immunopositive. The frequent localization of DBI in cells, also known to contain large amounts of mitochondrial benzodiazepine receptors, indicates that DBI may play an important role as an endogenous regulator of intracellular metabolic functions via the mitochondrial benzodiazepine receptor.
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PMID:Immunohistochemistry of diazepam binding inhibitor (DBI) in the central nervous system and peripheral organs: its possible role as an endogenous regulator of different types of benzodiazepine receptors. 166 66

Delivery of cholesterol 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 benzodiazepine, 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 corticotropin-induced 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.
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PMID: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. 254 79

Benzodiazepines, which are in extensive clinical use, can regulate neoplastic growth via benzodiazepine receptors. We have studied the expression of the diazepam binding inhibitor (DBI) polypeptide, a putative endogenous ligand for benzodiazepine receptors in normal and pathological human brain. In normal brain, DBI immunoreactivity (IR) and mRNA were detected in all brain areas, with the highest levels in the cerebellum, amygdala, and hippocampus. In light and electron microscope immunohistochemistry, DBI-IR was only detected in glial and ependymal cells. In brain tumors, such as astrocytomas, glioblastomas and medulloblastomas, a much higher content of DBI-IR and -mRNA was found in normal tissues. The highest level of DBI expression was found in the most anaplastic tumors. DBI-IR was virtually undetectable in meningiomas and pituitary adenomas. The high expression of DBI in brain tumors might play a role in the neoplastic growth of glial cells via the mitochondrial benzodiazepine receptor, or it may be involved in the regulation of the high energy consumption of these tumors via acyl-CoA metabolism.
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PMID:Increased expression of diazepam binding inhibitor in human brain tumors. 779 98

A recognition site for benzodiazepines structurally different from that linked to the gamma-aminobutyric acid receptor subtype A or the "central type" benzodiazepine receptor has been located mainly in the outer membranes of mitochondria and designated mitochondrial benzodiazepine receptor (MBR). A putative endogenous ligand for MBR is the peptide, diazepam binding inhibitor (DBI), which inhibits benzodiazepine ligand binding in mitochondrial membranes. In this study, DBI- and MBR-like immunoreactivities (LI) were examined at the cellular and ultrastructural levels, and their changes during cell growth were followed in rat primary cerebellar astroglial and C-6 cell cultures. During the early stages of the cultures (7-14 days in vitro), MBR and DBI were expressed virtually in all astrocytes and C-6 cells of the cultures. The highest MBR/DBI immunoreactivity was observed in dividing cells. When the astrocytes had formed a confluent layer (21 days in vitro), MBR staining intensity was significantly decreased. Electron microscopic analysis demonstrated an even distribution of DBI-LI throughout the cytoplasm, while MBR-LI was mainly observed in a close association with the outer mitochondrial membranes. However, dividing cells also displayed strong MBR immunoreactivity in endoplasmic reticulum, nuclear membranes, and centrioles. Treatment of the confluent cultures with MBR ligands PK 11195 and Ro 5-4864 at nanomolar concentrations increased the density of MBR-LI and the progesterone content in the medium 2-3-fold over the basal levels. These results demonstrate a close association between DBI and mitochondrial benzodiazepine receptors and lend support to the theory that they have a possible role in the regulation of steroid production. The relation of MBR and DBI expression to cell growth and division suggests a novel role for these elements in the regulation of important intracellular events.
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PMID:Expression of mitochondrial benzodiazepine receptor and its putative endogenous ligand diazepam binding inhibitor in cultured primary astrocytes and C-6 cells: relation to cell growth. 781 26

The peripheral-type benzodiazepine receptor (pBZD-R; also called the omega-3 receptor or the mitochondrial benzodiazepine receptor) seems to play a critical role in the production of neurosteroids, which are able to alter the electrical properties of neuronal membranes and thus the firing patterns of neurons. Putative endogenous ligands are the diazepam-binding inhibitor and its processing products, as well as porphyrins, some of them, in the case of porphyria, are well known to give rise to certain aspects of neuropsychiatric disorders, such as schizophrenic-like symptoms. Previous findings of altered benzodiazepine binding sites in post-mortem brain samples and platelets from small samples of schizophrenic patients have been inconclusive. Therefore we investigated characteristic binding parameters (Bmax, Kd) of the granulocytic pBZD-R by using the selective ligand PK11.195 in 53 subjects, fulfilling ICD-10 and DSM-IV criteria of schizophrenia. The binding parameters in our total group of 53 schizophrenic patients did not differ from those in healthy subjects. However, Bmax values were significantly reduced in schizophrenic patients with predominantly negative symptoms (residual type) compared to schizophrenic patients with predominantly positive symptoms, i.e. paranoid (-50%) and catatonic subtype (-38%). Moreover, only residual type schizophrenics exhibited a significantly reduced binding capacity compared to healthy subjects (-38%). More studies are warranted to clarify the functional significance of this binding site in the pathogenesis of negative symptoms.
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PMID:Peripheral-type benzodiazepine receptors in diagnostic subtypes of schizophrenic patients. 992 87