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At least 19 recordsLinked to original sources
PubMed1990

A natural processing product of rat diazepam binding inhibitor, triakontatetraneuropeptide (diazepam binding inhibitor 17-50) contains an alpha-helix, which allows discrimination between benzodiazepine binding site subtypes.

Synthetic peptides related to triakontatetraneuropeptide (TTN) [17TQPTDEEMLFIYSHFKQATVGDVNTDRPGLLDLK50; diazepam binding inhibitor (DBI) 17-50], a natural brain processing product of rat DBI, were analyzed for their physicochemical and ligand-receptor interaction characteristics. The ability of TTN and TTN-related fragments to displace [3H]flumazenil (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol[1,5a] [1,4]-benzodiazepine-3-carboxylate) or [3H]Ro 5-4864 [7-chloro-1,3-dihydro-1-methyl-5-(p-chlorophenyl)-2H-1, 4-benzodiazepine-2-one] from their respective benzodiazepine (BZ) binding site subtypes was tested in intact cerebellar culture neurons or in homogenates of cultured astrocytes. These studies indicate that the C-terminal region of TTN, which is also present in DBI 22-50, eicosapentaneuropeptide (DBI 26-50), and octadecaneuropeptide (ODN) (DBI 33-50), but not in DBI 19-41, is essential for interaction with the BZ recognition sites. When the C-terminal lysine of ODN is blocked with an NH2 group, the ability of ODN to interact with the binding of [3H]flumazenil is lost. A comparison analysis of the binding data with the secondary structure characteristics of the peptides demonstrated that TTN (DBI 17-50) and DBI 22-50, which have hydrophobic portions and marked tendencies to produce alpha-helicity, specifically displace (apparent Ki, 5-6 microM) [3H] Ro 5-4864 from astroglial cell binding sites. Peptides (ODN, eicosapentaneuropeptide, OND-NH2) with very low tendencies to form alpha-helices and with virtually no hydrophobic structure were not able to displace Ro 5-4864 at concentrations of up to 100 microM. In contrast, ODN was a good displacer of [3H]flumazenil from intact neurons, with an apparent IC50 of 5 microM. These data suggest that the alpha-helical portion of TTN may be important for BZ receptor recognition and BZ receptor subtype discrimination.

Amino Acid Sequence↗
PubMed1987

Subcellular location and neuronal release of diazepam binding inhibitor.

Diazepam binding inhibitor (DBI), a peptide located in CNS neurons, blocks the binding of benzodiazepines and beta-carbolines to the allosteric modulatory sites of gamma-aminobutyric acid (GABAA) receptors. Subcellular fractionation studies of rat brain indicate that DBI is compartmentalized. DBI-like immunoreactivity is highly enriched in synaptosomes obtained by differential centrifugation in isotonic sucrose followed by a Percoll gradient. In synaptosomal lysate, DBI-like immunoreactivity is primarily associated with synaptic vesicles partially purified by differential centrifugation and continuous sucrose gradient. Depolarization induced by high K+ levels (50 mM) or veratridine (50 microM) released DBI stored in neurons of superfused slices of hypothalamus, hippocampus, striatum, and cerebral cortex. The high K+ level-induced release is Ca2+ dependent, and the release induced by veratridine is blocked by 1.7 microM tetrodotoxin. Depolarization released GABA and Met5-enkephalin-Arg6-Phe7 together with DBI. DBI is also released by veratridine depolarization, in a tetrodotoxin-sensitive fashion, from primary cultures of cerebral cortical neurons, but not from cortical astrocytes. Depolarization fails to release DBI from slices of liver and other peripheral organs. These data support the view that DBI may be released as a putative neuromodulatory substance from rat brain neurons.

Animals↗
PubMed1993

Inhibition of hormone-stimulated steroidogenesis in cultured Leydig tumor cells by a cholesterol-linked phosphorothioate oligodeoxynucleotide antisense to diazepam-binding inhibitor.

The polypeptide diazepam-binding inhibitor (DBI) has been previously shown to stimulate testicular Leydig, adrenocortical, and glial-cell mitochondrial steroidogenesis in vitro. To assess the in situ role of DBI in trophic hormone-stimulated steroidogenesis, we suppressed DBI levels in the hormone-responsive MA-10 Leydig tumor cells, using a cholesterol-linked phosphorothioate oligodeoxynucleotide (Chol-odN) antisense to DBI. Treating MA-10 cells with Chol-odN antisense to DBI resulted in a dose-dependent reduction of DBI levels (ED50 = 1 microM). In contrast, Chol-odN sense to DBI did not affect its expression. Saturating amounts of human choriogonadotropin (hCG) increased MA-10 progesterone production by 150-fold. Addition of increased concentrations of Chol-odNs sense to DBI or of a nonrelated sequence did not reduce the MA-10 response to hCG. However, in the presence of Chol-odN antisense to DBI that could reduce DBI levels, MA-10 cells lost their ability to respond to hCG (ED50 = 1 microM). In these studies the hCG-stimulated cAMP levels and cytochrome P450 side-chain cleavage activity, as measured by metabolism of 22(R)-hydroxycholesterol, were not affected by the Chol-odNs used. These observations provide unequivocal evidence that DBI plays a vital role in the acute stimulation of steroidogenesis by trophic hormones.

Animals↗
PubMed1991

Diazepam binding inhibitor peptide: cloning and gene expression.

Diazepam binding inhibitor (DBI) is a peptide, initially identified for its ability of displacing the binding of diazepam. The screening of lambda gt 10 cDNA libraries from rat brain with a 47merdeoxyoligonucleotide probe, complementary to a small portion of DBI coding region, allowed the isolation of cDNA clones encoding the entire aminoacid sequence of DBI. This sequence, when compared to that of mouse, human and bovine, revealed that DBI is a well conserved peptide, suggesting a similar function in different species. In order to characterize the function of DBI, studies on the regulation of DBI gene expression were undertaken. The expression of DBI mRNA occurs unevenly in the brain, as well as in peripheral tissues. Moreover, the biosynthesis of DBI is up-regulated in the cerebellum and cerebral cortex of rats made tolerant to diazepam, suggesting that changes in the biosynthesis of DBI might be one of the mechanisms eliciting tolerance to benzodiazepine. In peripheral tissues, the expression of DBI mRNA changes during development. In liver, the content of DBI mRNA was found maximal at postnatal day 1. In contrast, in kidney and heart a linear increase in levels of DBI mRNA was observed from postnatal day 1 to the adult stage, where it reached its maximum level. The tissue specific regulation of DBI mRNA expression, both pharmacologically or developmentally, leads to the hypothesis that DBI might have different functions in different tissues. This would be in line with recent findings that DBI might be also involved in the regulation of an important step of cell metabolism.

Amino Acid Sequence↗
PubMed1989

Sequence and expression of the murine diazepam binding inhibitor.

Previous studies suggest that a diazepam binding inhibitor (DBI, also referred to as endozepine) present in the brain may function anxiogenically as a modulator of the gamma-aminobutyric acid receptor complex (GABAA). An expression library representing mouse brain mRNA was screened using antisera that recognizes the 11 kDa DBI protein. A cDNA clone was isolated and sequenced. Comparison of the amino acid sequence of mouse DBI to that for human, rat and bovine DBI shows that the size of DBI is conserved at 87 amino acids in all of these mammals. DBI cDNA hybridizes to an mRNA of about 600 nucleotides. This mRNA is not restricted to the brain, being prevalent in other organs such as the liver and kidney. Its moderate to high abundance, as judged from mRNA levels, in several organs suggests that DBI might have functions other than, or in addition to, the possible regulation of benzodiazepine binding sites.

Amino Acid Sequence↗
PubMed1992

CSF diazepam-binding inhibitor concentrations in panic disorder.

Diazepam-binding inhibitor (DBI) is a neuropeptide that has been detected in the brain and cerebrospinal fluid (CSF). Previous studies have suggested the possible role of DBI as a potential endogenous anxiogenic ligand modulating GABAergic transmission at the benzodiazepine-GABA receptor complex. The measurement of DBI immunoreactivity (DBI-IR) in CSF of panic-disorder patients and normal controls was undertaken to assess whether there were differences in the CSF concentration of this peptide to assess possible relationships with other monoamines and peptides. Lumbar CSF was obtained from 18 panic patients (4 men, 14 women) and 9 controls (5 men, 4 women). As a group, no significant differences were found between panic patients' CSF concentration of DBI-IR (1.12 +/- 0.27 pmol/mL) and normal volunteers (1.23 +/- 0.27 pmol/mL). No gender differences were demonstrated. However, we did find a positive correlation between CSF levels of DBI and CSF corticotropin releasing hormone (CRH) in our panic patients.

Adult↗
PubMed1998

Regulation of the action of the novel cholecystokinin-releasing peptide diazepam binding inhibitor by inhibitory hormones and taurocholate.

Diazepam binding inhibitor (DBI1-86) has recently been isolated in search for a cholecystokinin (CCK)-releasing peptide in the duodenum that is responsible for the feedback regulation of exocrine pancreatic secretion. Synthetic porcine DBI1-86 stimulates CCK release in vivo and in vitro from isolated intestinal mucosal cells. We postulated that DBI intraduodenally releases CCK in a paracrine fashion and might be the missing link in the feedback regulation of exocrine pancreatic secretion. Somatostatin, peptide YY (PYY) and taurocholate are known to inhibit feedback-stimulated CCK release in the rat. In this study, we investigated the effect of somatostatin, PYY and taurocholate on DBI-stimulated CCK secretion. Dispersed rat intestinal mucosal cells were prepared from the proximal small bowel and continuously perfused. The perfusate was collected and the release of CCK into the medium was measured. DBI1-86 dose-dependently stimulated CCK release, with a maximal effect at 10(-9) M. Somatostatin blocked the DBI-stimulated CCK release. Pretreatment of the cells with pertussis toxin fully reversed the inhibitory effect of somatostatin on DBI-stimulated CCK secretion, suggesting that somatostatin exerts its action by an inhibitory G-protein. In contrast, PYY (10(-6) M) and taurocholate (10(-6) M) did not affect DBI stimulated CCK levels, indicating that they act through different mechanisms to inhibit feedback-stimulated CCK release.

Animals↗
PubMed1986

Diazepam-binding inhibitor. A brain neuropeptide present in human spinal fluid: studies in depression, schizophrenia, and Alzheimer's disease.

Diazepam-binding inhibitor is a novel peptide purified to homogeneity from rat and human brain. Diazepam-binding inhibitor is present, though not exclusively, in gamma-aminobutyric acid (GABA)-containing neurons where it is believed to inhibit GABAergic neurotransmission mediated by GABA by binding to the benzodiazepine-GABA receptor complex. Since an impairment of central GABAergic tone has been postulated to be associated with a number of neuropsychiatric disorders, we measured human diazepam-binding inhibitor immunoreactivity in the cerebrospinal fluid (CSF) of patients suffering from endogenous depression, schizophrenia, and dementia of the Alzheimer's type. Patients with major depression had significantly higher concentrations of human diazepam-binding inhibitor immunoreactivity in CSF when compared with age- and sex-matched normal volunteers, while no difference in CSF diazepam-binding inhibitor immunoreactivity was found in schizophrenics or patients with dementia of the Alzheimer's type when compared with controls. The possibility is discussed that the increased CSF human diazepam-binding inhibitor immunoreactivity observed in depressed patients may represent a functional disinhibition of GABAergic neurotransmission associated with depression.

Adult↗
PubMed1991

Cerebrospinal fluid diazepam binding inhibitor in depressed patients and normal controls.

Diazepam binding inhibitor (DBI) is a neuromodulatory peptide for gamma-aminobutyric acid (GABA) neurotransmission. Levels of DBI in cerebrospinal fluid (CSF) were found to be elevated in depressed patients, when compared to age- and sex-matched normal controls. Levels of the peptide, corticotropin-releasing hormone (CRH), in CSF have been found to be elevated in depressed patients. Significant positive correlations between levels of DBI and CRH in the CSF of depressed patients and normal controls were found. These data suggest the possibility that DBI may have a role in coordinating responses to stress in humans, in addition to its possible role in the pathophysiology of depression.

Adult↗
PubMed1993

Cloning and tissue-specific functional characterization of the promoter of the rat diazepam binding inhibitor, a peptide with multiple biological actions.

Diazepam binding inhibitor (DBI) is a 10-kDa polypeptide that regulates mitochondrial steroidogenesis, glucose-induced insulin secretion, metabolism of acyl-CoA esters, and the action of gamma-aminobutyrate on GABAA receptors. To investigate the regulation of DBI gene expression, three positive clones were isolated from a rat genomic library. One of them contained a DBI genomic DNA fragment encompassing 4 kb of the 5' untranslated region, the first two exons, and part of the second intron of the DBI gene. Two other overlapping clones contained a processed DBI pseudogene. Several transcription initiation sites were detected by RNase protection and primer extension assays. Different tissues exhibited clear differences in the efficiencies of transcription startpoint usage. Transient expression experiments using DNA fragments of different length from the 5' untranslated region of the DBI gene showed that basal promoter activity required 146 bp of the proximal DBI sequence, whereas full activation was achieved with 423 bp of the 5' untranslated region. DNase I protection experiments with liver nuclear proteins demonstrated three protected regions at nt -387 to -333, -295 to -271, and -176 to -139 relative to the ATG initiation codon; in other tissues the pattern of protection was different. In gel shift assays the most proximal region (-176 to -139) was found to bind several general transcription factors as well as cell type-restricted nuclear proteins which may be related to specific regulatory patterns in different tissues. Thus, the DBI gene possesses some features of a housekeeping gene but also includes a variable regulation which appears to change with the function that it subserves in different cell types.

Animals↗
PubMed1989

Cerebrospinal fluid content of diazepam binding inhibitor in chronic hepatic encephalopathy.

The neuropeptide diazepam binding inhibitor (DBI) is an endogeneous allosteric modulator of gamma-aminobutyric acid (GABA) receptors at the benzodiazepine recognition site. Recent theories on the neurochemical cause for hepatic encephalopathy have implicated activation of inhibitory neurotransmitter GABA systems. In 20 patients with hepatic disease, blood and cerebrospinal fluid (CSF) levels of ammonia and amino acids were measured. As in previous studies there was a selective elevation of CSF amino acids as well as a correlation between CSF glutamine levels and encephalopathy. CSF DBI levels were maximally elevated 5-fold in patients with hepatic encephalopathy, but they were normal in those patients with liver disease not associated with changes in mental status and in patients with nonhepatic encephalopathy. Levels of DBI correlated with the clinical staging of hepatic encephalopathy. These data suggest that DBI may participate in the modulation of cerebral function in hepatic encephalopathy.

Adult↗
PubMed1990

CSF diazepam-binding inhibitor in alcoholics and normal controls.

Diazepam-binding-inhibitor (DBI) and gamma-aminobutyric acid (GABA) are colocalized in neurons in the brain. This system has been implicated in anxiety and in the regulation of corticotropin-releasing hormone (CRH) secretion. Alcohol has direct and indirect effects on the functioning of GABAA receptors. Abstinent alcoholics are, on the average, more anxious than controls. In tests of animal behavior, DBI has anxiogenic, and alcohol has anxiolytic potency. Therefore, we compared alcoholic patients and healthy controls for cerebrospinal fluid (CSF) levels of DBI, and looked for a correlation between CSF levels of DBI and CRH. There was no significant difference in CSF concentrations of DBI between the two groups and no significant correlation between CSF DBI and our measure of anxiety. However, there was a significant positive correlation between CSF levels of DBI and CRH in both the alcoholic and control groups.

Adult↗
PubMed1991

Regulation of diazepam binding inhibitor in rat adrenal gland by adrenocorticotropin.

Diazepam binding inhibitor (DBI) is a 9-kDa polypeptide that was initially isolated from rat brain and subsequently found to be present in several peripheral tissues. DBI is particularly abundant in steroidogenic tissues, such as the adrenal glands and testes, which also contain a high concentration of peripheral/mitochondrial benzodiazepine receptors (MBRs). Because occupancy of adrenal MBRs with DBI results in increased steroidogenesis, we have investigated the relation between ACTH, DBI, and the MBR in the rat adrenal glands. Evidence presented here indicates that both the amount of DBI and its rate of synthesis in the adrenal cortex are under the control of ACTH. Seven and 9 days after hypophysectomy, the amount of DBI-like immunoreactivity (DBI-LI) in rat adrenal glands decreased dramatically from approximately 80 to 15 ng/mg tissue. The administration of single dose of ACTH (ACTH residues 1-39; 200 mU/kg, iv) or repeated doses of ACTH-R (ACTH in saline containing 16% gelatin; 15 U/kg, sc, twice daily) reduced the decrease in adrenal DBI-LI caused by hypophysectomy. In hypophysectomized rats (7 days after hypophysectomy) the increases in both adrenal DBI-LI and plasma corticosterone induced by ACTH 1 h after a single injection (200 mU/kg, iv) were inhibited by injection of cycloheximide (40 mg/kg, ip) 10 min after ACTH. However, cycloheximide at this dose had no effect on the ACTH-induced increase in adrenal cAMP concentration or the number of affinity of MBRs for 4'-[3H]chlorodiazepam.

Adrenal Glands↗
PubMed1995

Inhibitory effect of ODN, a naturally occurring processing product of diazepam binding inhibitor, on secretagogues-induced insulin secretion.

Diazepam binding inhibitor (DBI1-86) is a peptide that is present in large amounts in the intestine and pancreas and which inhibits glucose-stimulated insulin release from both perfused pancreas and isolated islets in low nanomolar concentrations. Here, DBI33-50 (also known as ODN, octadecaneuropeptide), one of the naturally occurring processing products of DBI1-86, and certain synthetic modified derivatives, have been shown to inhibit glucose and glibenclamide-stimulated insulin secretion from isolated rat islets and glibenclamide-stimulated insulin secretion from hamster-insulinoma (HIT-T15) beta-cell line. DBI17-50 (TTN; triakontatetraneuropeptide), another prominent processing product of DBI, had no effect. The 50% inhibitory concentration (IC50) for the effect of ODN on insulin secretion induced by 8.3 of 16.7 mM glucose was approximately the same: 5 to 6 nM. Moreover, ODN inhibited insulin release induced by 0.01 or 1 microM glibenclamide with a similar IC50 (8 to 10 nM) in both isolated pancreatic islets and in HIT-T15 beta-cells. At concentration up to 1 microM, ODN had no effect on insulin secretion induced by PACAP (pituitary adenylate cyclase polypeptide), BAYK 8644 (methyl-(1,4-dihydro-2,6-dimethyl-3-nitro-4,2-trifluoromethylphenyl) pyridine-5-carboxylate), and only marginally it affected IBMX-(isobutylmethylxanthine) induced insulin secretion. This indicates that ODN does not act directly on ATP-regulated K+ channels, voltage dependent Ca2+ channels or cAMP production. In contrast, ODN inhibited insulin secretion induced by sodium nitroprussiate in a manner that is independent from the presence of extracellular Ca2+. These results suggest that ODN or ODN-like peptide fragments of DBI, may inhibit glucose or glibenclamide-induced insulin secretion via a signaling pathway that regulate the cytoplasmic free Ca2+ concentration.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Molecular biology of diazepam binding inhibitor.

The techniques of molecular biology have rapidly advanced the field of neuropharmacology in recent years. Some of these advantages are presented briefly, followed by an example of the power of nucleic acid analysis: specifically the characterization of the diazepam binding inhibitor (DBI). The diazepam binding inhibitor is a putative endogenous ligand for a regulatory site on the gamma-aminobutyric acid, type A receptor. The complementary deoxyribonucleic acid (cDNA) encoding this 87-residue peptide has been isolated, sequenced and expressed in heterologous systems. Diazepam binding inhibitor is encoded by a multigene family and is expressed in a tissue-specific manner, although expression is not limited to the brain.

Amino Acid Sequence↗
PubMed1991

Diazepam binding inhibitor (DBI): a peptide with multiple biological actions.

Diazepam binding inhibitor (DBI) is a 9-kD polypeptide that was first isolated in 1983 from rat brain by monitoring its ability to displace diazepam from the benzodiazepine (BZD) recognition site located on the extracellular domain of the type A receptor for gamma-aminobutyric acid (GABAA receptor) and from the mitochondrial BZD receptor (MBR) located on the outer mitochondrial membrane. In brain, DBI and its two major processing products [DBI 33-50, or octadecaneuropeptide (ODN) and DBI 17-50, or triakontatetraneuropeptide (TTN)] are unevenly distributed in neurons, with the highest concentrations of DBI (10 to 50 microMs) being present in the hypothalamus, amygdala, cerebellum, and discrete areas of the thalamus, hippocampus, and cortex. DBI is also present in specialized glial cells (astroglia and Bergmann glia) and in peripheral tissues. In the periphery, the highest concentration of DBI occurs in cells of the zona glomerulosa and fasciculata of the adrenal cortex and in Leydig cells of the testis; interestingly, these are the same cell types in which MBRs are highly concentrated. Stimulation of MBRs by appropriate ligands (including DBI and TTN) facilitates cholesterol influx into mitochondria and the subsequent formation of pregnenolone, the parent molecule for endogenous steroid production; this facilitation occurs not only in peripheral steroidogenic tissues, but also in glial cells, the steroidogenic cells of the brain. Some of the steroids (pregnenolone sulfate, dehydroepiandrosterone sulfate, 3 alpha-hydroxy-5 alpha-pregnan-20-one, and 3 alpha, 21-dihydroxy-5 alpha-pregnan-20-one) produced in brain (neurosteroids) function as potent (with effects in the nanomolar concentration range) positive or negative allosteric modulators of GABAA receptor function. Thus, accumulating evidence suggests that the various neurobiological actions of DBI and its processing products may be attributable to the ability of these peptides either to bind to BZD recognition sites associated with GABAA receptors or to bind to glial cell MBRs and modulate the rate and quality of neurosteroidogenesis. The neurobiological effects of DBI and its processing products in physiological and pathological conditions (hepatic encephlopaty, depression, panic) concentrations may therefore be explained by interactions with different types of BZD recognition site. In addition, recent reports that DBI and some of its fragments inhibit (in nanomolar concentrations) glucose-induced insulin release from pancreatic islets and bind acyl-coenzyme A with high affinity support the hypothesis that DBI isa precursor of biologically active peptides with multiple actions in the brain and in peripheral tissues.

Amino Acid Sequence↗
PubMed1991

Diazepam binding inhibitor (DBI) increases after acute stress in rat.

Diazepam binding inhibitor (DBI) acts in brain by binding to GABAA/benzodiazepine receptors (GBR) and to mitochondrial benzodiazepine receptors (MBR). Because DBI acting at MBR, has been shown to be an effector of ACTH-induced steroidogenesis and stress is known to change the level of GBR and MBR, the model of acute noise stress in rats was used to study modifications of DBI and GRB or the content of MBR in various areas of the brain and adrenal gland. It was found that, in the brain of stressed rats, DBI and its processing products (ODN-like immunoreactivity), increased selectively in the hippocampus. This increase in the content of DBI was preceded and followed by a net decrease of GBR and an increase of MBR. Similarly, in adrenal cortex, the content of DBI and MBR increased during the first hour, following acute stress and this increase paralleled the increase in plasma corticosterone. These data suggest that DBI, acting on MBR may regulate steroidogenic function in stress.

Adrenal Glands↗