Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P30536 (PBS)
9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitochondrial benzodiazepine receptor (mBzR) has been solubilized with retention of reversible ligand binding, and the associated subunits were characterized. mBzR comprises immunologically distinct protein subunits of 18-, 30-, and 32-kDa. The 18-kDa protein is labeled by the isoquinoline carboxamide mBzR ligand [3H]PK14105, whereas the 30- and 32-kDa subunits are labeled by the benzodiazepine (Bz) ligands [3H]flunitrazepam and [3H]AHN-086. Selective antibodies and reagents identify the 32- and 30-kDa proteins as the voltage-dependent anion channel (VDAC) and the adenine nucleotide carrier (ADC), respectively. While isoquinoline carboxamide and Bz ligands target different subunits, they interact allosterically, as the binding of Bz and isoquinoline carboxamide ligands is mutually competitive at low nanomolar concentrations. Moreover, eosin-5-maleimide and mercuric chloride inhibit [3H]PK11195 binding to the intact receptor via sulfhydryl groups that are present in ADC. VDAC and ADC, outer and inner mitochondrial membrane channel proteins, respectively, together with the 18-kDa subunit, may comprise mBzR at functionally important transport sites at the junction of two mitochondrial membranes.
...
PMID:Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. 137 86

The isoquinoline carboxamide photoaffinity probe PK14105, a ligand with selectivity for mitochondrial benzodiazepine receptors, has been established to photolabel an 18-kDa protein. When this radioactive probe is used to photolabel rat mitochondrial preparations, a protein of 10 kDa, in addition to the 18-kDa protein, is identified following electrophoretic separation and extended autoradiography. These proteins are referred to herein as pk10 and pk18, respectively. Both proteins exhibited the same specificity to a series of ligands used in competition photolabeling studies and are mutually present at apparently similar ratios across multiple tissues. Subcellular fractionation of rat adrenals indicated that pk10 and pk18 comigrated with the mitochondrial marker enzyme cytochrome c oxidase. In numerous paradigms examining specificity, photolabeling of pk18 invariably coincided with photolabeling of pk10. In detergent-solubilized extracts of rat adrenal mitochondria, pk18 and pk10 coimmunoprecipitated when using antisera raised against pk18. Furthermore, purification of the photolabeled proteins using nondenaturing conditions demonstrated that pk18 and pk10 copurify substantiating their intimate association. A set of three antisera, specific to different regions of pk18, did not recognize pk10 on Western blots. Likewise, partial amino acid sequence of peptide fragments indicate that pk10 is not derived from proteolytic cleavage of pk18. These data suggest that pk10 represents another component of mitochondrial benzodiazepine receptors whose identity is not apparent with any known protein.
...
PMID:Identification and purification of a 10-kilodalton protein associated with mitochondrial benzodiazepine receptors. 765 98

The effect of peripheral-type benzodiazepines on dog neutrophil stimulation was studied. Ro 5-4864 (a specific ligand of mitochondrial benzodiazepine receptor) and diazepam (which binds both to mitochondrial and central benzodiazepine receptors) did not show any direct toxic effect against neutrophils. PK 11195, a putative antagonist of the mitochondrial benzodiazepine receptor and an isoquinoline derivative, had a direct toxic effect at a concentration of 5 x 10(-5) M (72% of cells were viable). Ro 5-4864 (10(-6)-10(-4) M) and diazepam (10(-6)-2.5 x 10(-4) M) induced an intracellular oxidative stress in dog neutrophils. These compounds, in a micromolar range, also induced a concentration-dependent cell surface expression of heat shock protein (HSP) families. The percentages of positive cells that express these proteins were: 76.2% for HSP 27 kDa; 54.3% for HSP 72 kDa and 69.6% for HSP 90 kDa for Ro 5-4864 (10(-4) M), and 66.7% for HSP 27 kDa; 45.4% for HSP 72 kDa and 78.3 for HSP 90 kDa for diazepam (2.5 x 10(-4) M). It appears that this HSP expression, induced by peripheral-type benzodiazepines could be mediated by an intracellular oxidative stress.
...
PMID:Cell surface expression of heat shock proteins in dog neutrophils induced by mitochondrial benzodiazepine receptor ligands. 777 58

The purified mitochondrial benzodiazepine receptor (mBzR) is a complex comprising the voltage-dependent anion channel (VDAC), adenine nucleotide carrier, and an 18-kDa protein that binds isoquinoline carboxamide ligands (McEnery, M. W., Snowman, A. M., Trifiletti, R. R., and Snyder, S. H. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 3170-3174). An antiserum raised against the mBzR complex reacts selectively with VDAC and is used, along with purification, electrophysiological and immunohistochemical techniques, to characterize the properties and distribution of rat brain VDAC. Although purified VDAC displays biochemical and electrical conductance properties similar to VDAC from other sources, the immunohistochemical distribution of VDAC in rat brain is heterogeneous with pronounced regional variations; the pontine nuclei, the supraoptic nucleus, Purkinje cells of the cerebellum, and the caudate putamen evidence the highest density. The distribution of VDAC is inclusive of the more discretely localized 18-kDa mBzR protein, suggesting that only a portion of the total VDAC participates in the mBzR. The histochemical localizations of the mitochondrial marker enzymes glutamate dehydrogenase and cytochrome c oxidase also indicate marked regional variability in both mitochondrial content and composition. The discrete expression of VDAC reflects a striking heterogeneity of rat brain mitochondria and underlying differences in the utilization of mitochondrial outer membrane ion channels.
...
PMID:Mitochondrial voltage-dependent anion channel. Immunochemical and immunohistochemical characterization in rat brain. 822 52

Using RT-PCR, gene expression of the peripheral-type benzodiazepine receptor isoquinoline carboxamide-binding protein (PTBR-IBP) was studied in the frontal cortex of rats four weeks following end-to-side portacaval anastomosis, an experimental animal model of hepatic encephalopathy, or sham operation. Portacaval anastomosis resulted in increased expression of PTBR-IBP in frontal cortex and in a concomitant increase in densities (Bmax) of binding sites for the PTBR ligand [3H]PK11195. In view of the findings that the PTBR modulates the synthesis of neurosteroids with high affinity for excitatory and inhibitory neurotransmitter systems in brain, increased expression of these receptors could be implicated in the pathogenesis of hepatic encephalopathy.
...
PMID:Increased expression of the peripheral-type benzodiazepine receptor-isoquinoline carboxamide binding protein mRNA in brain following portacaval anastomosis. 920 58

The peripheral type benzodiazepine receptor (PBR) binds benzodiazepines such as RO5-4864 and isoquinoline carboxamide derivatives such as PK11195. This receptor includes an Mr 18,000 isoquinoline-binding subunit predominantly located in mitochondrial mem- branes. This protein has been found to copurify with two other mitochondrial proteins, namely the outer membrane voltage-dependent anion channel (VDAC), also known as mitochondrial porin, and the inner membrane adenine nucleotide carrier. In vitro reconstitution experiments suggested that the PBR was a multimeric complex in which the isoquinoline binding site was on the Mr 18,000 subunit, denoted pk18, whereas the benzodiazepine binding site required the association of this subunit with VDAC to be expressed. Untransformed cells of the yeast Saccharomyces cerevisiae are devoid of specific binding sites for isoquinolines and benzodiazepines, whereas yeast cells transformed with a pk18-expressing vector exhibit RO5-4864 and PK11195 binding sites that are pharmacologically identical to those of the PBR. To clarify the role of VDAC and of the adenine nucleotide carrier, if any, in the constitution of the benzodiazepine binding site, yeast host strains were constructed in which the corresponding genes had been knocked out. Mitochondria prepared from pk18-producing cells devoid of either VDAC or adenine nucleotide carrier exhibit both benzodiazepine and isoquinoline carboxamide binding sites with little or no change in the Kd values as compared with the wild-type background. These results rule out the contention that VDAC is indispensable for establishing the benzodiazepine binding site and are in agreement with the hypothesis that the Mr 18,000 subunit carries both the isoquinoline carboxamide and benzodiazepine binding domains.
...
PMID:The Mr 18,000 subunit of the peripheral-type benzodiazepine receptor exhibits both benzodiazepine and isoquinoline carboxamide binding sites in the absence of the voltage-dependent anion channel or of the adenine nucleotide carrier. 934 65

Increased levels of brain ammonia occur in both congenital and acquired hyperammonemic syndromes including hepatic encephalopathy, fulminant hepatic failure, Reye's syndrome and congenital urea cycle disorders. In addition to its effect on neurotransmission and energy metabolism, ammonia modulates the expression of various genes including the astrocytic "peripheral-type" benzodiazepine (or omega 3) receptor (PTBR). Increased expression of the isoquinoline carboxamide binding protein (IBP), one of the components of the PTBR complex, is observed in brain and peripheral tissues following chronic liver failure as well as in cultured astrocytes exposed to ammonia. Increased densities of binding sites for the PTBR ligand [3H]-PK11195 are also observed in these conditions as well as in brains of animals with acute liver failure, congenital urea cycle disorders and in patients who died in hepatic coma. The precise role of PTBR in brain function has not yet fully elucidated, but among other functions, PTBR mediates the transport of cholesterol across the mitochondrial membrane and thus plays a key role in the biosynthesis of neurosteroids some of which modulate major neurotransmitter systems such as the gamma-aminobutyric acid (GABA(A)) and glutamate (N-methyl-D-aspartate (NMDA)) receptors. Activation of PTBR in chronic and acute hyperammonemia results in increased synthesis of neurosteroids which could lead to an imbalance between excitatory and inhibitory neurotransmission in the CNS. Preliminary reports suggest that positron emission tomography (PET) studies using [11C]-PK11195 may be useful for the assessment of the neurological consequences of chronic liver failure.
...
PMID:The "peripheral-type" benzodiazepine (omega 3) receptor in hyperammonemic disorders. 1202 Jun 11

Opening of the permeability transition (PT) pore is a central feature of apoptosis induction by chemical stress. One component of the PT pore, the mitochondrial benzodiazepine receptor (mBzR), has recently received attention for its potential role in modulating PT pore function. Specifically, antagonistic ligands of the mBzR, such as 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide (PK11195), have been shown to sensitize Bcl-2 overexpressing cells to apoptosis induction by facilitating the opening of the PT pore and the subsequent loss of mitochondrial membrane potential (Deltapsim). We examined whether PK11195 can sensitize EW36, a human B-cell lymphoma cell line that over-expresses Bcl-2, to apoptosis induction and mitochondrial depolarization by environmental chemicals including mitochondrial toxicants. We found that, although EW36 cells are refractory to apoptosis induction by antimycin A, rotenone, pyridaben, alachlor, and carbonyl cyanide m-chlorophenylhydrazone (mClCCP), they are dramatically sensitized to induction of apoptosis by low concentrations of these same agents following pre-treatment with PK11195. The sensitization of EW36 cells is accompanied by a rapid and extensive loss of Deltapsim within a few hours following chemical exposure. Furthermore, using sodium arsenite, we examined the role of the c-Jun N-terminal kinase (JNK) pathway and protein synthesis in apoptosis induction in EW36. We found that, unlike untreated cells, EW36 cells treated with PK11195 no longer show an association of JNK pathway activation with apoptosis induction. Importantly, PK11195 eliminates a requirement for protein synthesis in chemically induced apoptosis in EW36 cells. These results show significant drug-mediated alteration of cell sensitivity and JNK pathway activation to environmental chemicals and mitochondrial toxicants, following ligation of the mBzR.
...
PMID:Reversal of Bcl-2-mediated resistance of the EW36 human B-cell lymphoma cell line to arsenite- and pesticide-induced apoptosis by PK11195, a ligand of the mitochondrial benzodiazepine receptor. 1475 1

In the CNS, microglia become activated, i.e. change their functional state and phenotype, in response to a wide variety of pathological stimuli. Since this activation is triggered at a very low threshold and at the same time remains territorially restricted, the spatial distribution of activated microglia can be used as a sensitive, generic measure of the anatomical localisation of ongoing disease processes. One protein complex, undetectable in resting microglia but highly up-regulated upon activation in vivo and in vitro, is the 'peripheral benzodiazepine binding site', as measured by binding of the isoquinoline derivate PK11195. Particularly numerous in the outer membrane of mitochondria, this binding site has also been referred to as the 'mitochondrial benzodiazepine receptor'. The de novo expression of this receptor by activated microglia suggests that the process of activation may be associated with important qualitative changes in the state of mitochondria. Here, we provide confocal light- and electron microscopic evidence that the activation of microglia indeed entails conspicuous mitochondrial alterations. In cultured rat microglia stained with the fluorescent probe, JC-1, a sensitive indicator of mitochondrial membrane potential, we demonstrate that stimulation by bacterial lipopolysaccharide and interferon-gamma increases the number of microglial mitochondrial profiles and leads to marked changes in their morphology. Prominent elongated, "needle-like" mitochondria are a characteristic feature of activated microglia in vitro. Electron microscopically, an abundance of abnormal profiles, including circular cristae or ring- and U-shaped membranes, are found. Our observations support the notion that the previously reported increase in microglial binding of PK11195, that labelled with carbon-11 ([11C] (R)-PK11195) has clinical use for the visualisation of activated microglia in vivo by positron emission tomography, may at least in part relate to an increased number and altered functional state of microglial mitochondria.
...
PMID:Mitochondria in activated microglia in vitro. 1590 60

A series of phosphorescent zwitterionic iridium(III) complexes, with 4-carboxy-2, 2'-bipyridine-4'-carboxylate (Hdcbpy) as ancillary ligand, Ir(C(wedge)N)(2)(Hdcbpy) (C(wedge)N = 1-phenylpyrazole (ppz), 1-phenyl-pyridine (ppy), 2-(4',6'-difluoro-phenyl)pyridine (dfppy), 1-phenyl-isoquinoline (piq), dibenzo[f,h]quinoxaline (dbq)), were prepared and characterized. Their photophysical properties were studied, and intense luminescence emissions were observed based on metal-to-ligand-charge-transfer ((3)MLCT), ligand-to-ligand charge-transfer ((3)LLCT), ligand-centered transitions ((3)LC, i.e., (3)pi --> pi*), or intraligand-charge-transfer ((3)ILCT) excited states, which were confirmed by theoretical calculations. The quantum yield of Ir(dfppy)(2)(Hdcbpy) is as high as 0.106 in aqueous solution. With Hdcbpy as a hydrophilic part, their amphiphilic structures as further confirmed by X-ray single crystal data endow them with different solubilities in phosphate buffer solution (PBS, pH 7.0). The compounds were successfully applied as luminescent dyes for cell imaging in aqueous solution. Their different stain ability in cell imaging was fairly well supported by the experimental data based on the measurement of oil/water partition coefficients and encapsulation/release with liposomes.
...
PMID:Zwitterionic iridium complexes: synthesis, luminescent properties, and their application in cell imaging. 2021 Mar 60


1 2 Next >>

---