Disease relevance of Tspo

• Ocular development was highly sensitive to periods of hypoxia through a mechanism blocked with the potent Bzrp ligand PK11195 [1].
• In search of a PBR functional antagonist that would facilitate the studies on the biological function of PBR, we screened a phage display library [2].
• Cholesterol binding at the cholesterol recognition/ interaction amino acid consensus (CRAC) of the peripheral-type benzodiazepine receptor and inhibition of steroidogenesis by an HIV TAT-CRAC peptide [3].
• PBR was also found to be expressed at high levels in aggressive metastatic human breast tumor biopsies compared with normal breast tissues [4].
• Increased PBR levels were associated with the degree of demyelination and temporal activation of glial cell types in different anatomical regions [5].

Psychiatry related information on Tspo

• Acute, maximal electroshock (MES) increased the density of PBR in mouse cerebral cortex as evidenced by a 30% increase in the Bmax of this archetypic ligand [6].

High impact information on Tspo

• [(3)H]Promegestone photoincorporated into recombinant PBR, and this labeling was displaced by cholesterol [3].
• The normal functional state of mitochondria was restored with PK11195, a specific ligand of the mitochondrial peripheral-type benzodiazepine receptor [7].
• In addition, the PBR-dependent MDA-231 cell proliferation was found to highly correlate (r = -0.99) with the PBR-mediated changes in nuclear membrane cholesterol levels [4].
• Subcellular localization with both antibodies and a fluorescent PBR drug ligand revealed that PBR from the MDA-231 cell line as well as from aggressive metastatic human breast tumor biopsies localized primarily in and around the nucleus [4].
• In this study, we examined the expression, characteristics, localization, and function of PBR in a battery of human breast cancer cell lines differing in their invasive and chemotactic potential as well as in several human tissue biopsies [4].

Chemical compound and disease context of Tspo

• Our findings indicate that brain PBR levels increased as a function of dose and duration of cuprizone treatment and it was detectable prior to observable demyelination [5].
• In this study, we evaluated the effect of several ligands active at the central-type and peripheral-type benzodiazepine receptor (BzR) (clonazepam, diazepam, PK11195 and Ro5-4864) on the growth and differentiation of B16 melanoma cells [8].
• By screening phage display libraries, we have identified peptides that displace the high-affinity PBR benzodiazepine drug ligand, Ro5-4864 (4'-chlorodiazepam) [9].
• In this study, we documented the effects of different peripheral benzodiazepine receptor (PBR) ligands: PK 11195, Ro5-4864 and the newly described SSR 180575 on the development of pulmonary inflammation in vivo [10].
• Ro 5-4864 (i.p.), a specific agonist for PBR, elicited tonic-clonic convulsions in EL mice 2.6-times more potently than in DDY mice with CD50s of 11.9 and 31.2 mg/kg for EL and DDY mice, respectively [11].

Biological context of Tspo

• The peripheral-type benzodiazepine receptor (PBR) is involved in many cellular functions, including steroidogenesis, oxidative processes, cellular proliferation, and apoptosis [12].
• To understand the mechanisms of PBR expression and regulation, we established an mRNA expression profile in mouse tissues and cell lines and subsequently mapped the transcription start site and characterized the promoter of the gene [12].
• Given the proposed role of the peripheral-type benzodiazepine receptor (PBR) in conferring a constitutively steroidogenic phenotype to the R2C cells, the current study was conducted to investigate the relationship between its expression in MA-10 and R2C cells and correlate it with the constitutive nature of R2C cell steroidogenesis [13].
• The present study examined the impact that specific Bzrp ligands have on oxygen homeostasis in the early mouse embryo [1].
• The peripheral benzodiazepine receptor (Bzrp) has been implicated in the control of several processes, including mitochondrial biogenesis and embryo development [1].

Anatomical context of Tspo

• Mitochondria isolated from cells treated with ODNs antisense, but not missense, to PBR failed to form pregnenolone and respond to either StAR or Tom/StAR proteins [14].
• Our findings indicate that PBR tissue mRNA levels are relatively high in kidney, spleen, muscle, lung, adrenal gland, thymus, and stomach; are intermediate in pancreas, uterus, prostate, heart, and testis; and are low in brain and liver [12].
• Relatively high levels of PBR mRNA were also observed in the steroid-synthesizing MA-10 mouse Leydig tumor cells compared with adrenocortical Y1 mouse cells and nonsteroidogenic NIH-3T3 mouse fibroblasts, although PBR protein levels were much higher in both steroidogenic cells compared with fibroblasts [12].
• The peroxisome proliferator perfluorodecanoic acid inhibits the peripheral-type benzodiazepine receptor (PBR) expression and hormone-stimulated mitochondrial cholesterol transport and steroid formation in Leydig cells [15].
• Moreover, this action of PFDA on PBR mRNA stability indicates a new mechanism of action of peroxisome proliferators distinct from the classic transcription-mediated regulation of target genes [15].

Associations of Tspo with chemical compounds

• Peripheral-type benzodiazepine receptor-mediated action of steroidogenic acute regulatory protein on cholesterol entry into leydig cell mitochondria [14].
• Secretory and glandular tissues, especially steroid hormone-producing cells, are particularly rich in PBR [12].
• Our studies show that PBR expression as measured by PK 11195 ligand binding and Western analysis is much higher in MA-10 cells than R2C cells [13].
• The induction of PBR/IBP mRNA was also observed in MEL cells induced with diazepam [16].
• The cDNA allows for the expression of active PBR/IBP, exhibiting a high affinity for isoquinoline carboxamide, [3H]PK11195, with Kd of 0.80 and 1.56 nM [16].

Physical interactions of Tspo

• Deletion of the C-terminal domain of PBR and mutation of the highly conserved among all PBR amino acid sequences Y152 of the CRAC domain resulted in loss of the ability of mutant recPBR to bind cholesterol [17].
• These results provide strong evidence that PBR is not a single protein receptor but a multimeric complex in which the IQ binding site is on the M(r) 18,000 subunit and expression of the BZ binding site requires both the M(r) 18,000 and 34,000 voltage-dependent anion channel subunits [18].

Other interactions of Tspo

• MA-10 mouse Leydig tumor cells were treated with and without oligodeoxynucleotides (ODNs) antisense to PBR and StAR followed by treatment with saturating concentrations of human choriogonadotropin [14].
• These data suggest that both StAR and PBR proteins are indispensable elements of the steroidogenic machinery and function in a coordinated manner to transfer cholesterol into mitochondria [14].
• In search of the proteins regulating PBR we identified a protein, PAP7, which interacts with PBR and the PKA regulatory subunit RIalpha, is present in adrenal and gonadal cells and is found in mitochondria [2].
• PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection [19].
• Diazepam binding inhibitor is a paracrine/autocrine regulator of Leydig cell proliferation and steroidogenesis: action via peripheral-type benzodiazepine receptor and independent mechanisms [20].

Analytical, diagnostic and therapeutic context of Tspo

• CONCLUSION: This is the first study to demonstrate that functional antagonism of coexpressed Bcl-X(L) and Mcl-1 proteins using the mBzR antagonist Pk11195 can facilitate apoptosis in cholangiocarcinoma following chemotherapy and radiotherapy [21].
• Pyropheophorbides and their metal complexes were synthesized to investigate their applications as nonradioactive peripheral benzodiazepine receptor (PBR) binding probes and photosensitizers for use in photodynamic therapy [22].
• Next, the distribution of PBR in MA-10 Leydig cells was further examined using confocal microscopy [20].
• First, PBR was immunolocalized in the rat testis using biotin-streptavidin peroxidase immunocytochemistry, and results revealed that PBR was present exclusively in the interstitial Leydig cells [20].
• To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR [23].

References