Structural and Functional Study of Reconstituted Peripheral Benzodiazepine Receptor

Lacapère, J; Delavoie, Franck; Li, Hua; Péranzi, Gabriel; Maccario, Jean; Papadopoulos, Vassilios; Vidić, Branislav

doi:10.1006/bbrc.2001.4975

Cited by 155 publications

(151 citation statements)

References 25 publications

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“…This model is consistent with the lower B max for Ro5-4864 and the observation that the voltage-dependant anion channel enhances Ro5-4864 binding but has no effect on PK11195 binding (Lacapere et al, 2001). We speculate that, similar to Ro5-4864, PBR28 binds only a fraction of TSPO molecules within the multimeric complex.…”

Section: Discussionsupporting

confidence: 86%

“…The TSPO exists both as a monomer and as part of a multimeric complex involving several TSPO monomers with associated proteins, including the voltage-dependent anion channel (Boujrad et al, 1994(Boujrad et al, , 1996Rao and Butterworth, 1997). Although subunit interactions are not necessary for drug ligands to bind the TSPO monomer (Joseph-Liauzun et al, 1997;Lacapere et al, 2001), binding of some drugs to the TSPO is influenced by these interactions (Golani et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Two Binding Sites for [³H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

Owen

Howell

Tang

et al. 2010

J Cereb Blood Flow Metab

190

194

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[11C]PBR28, a radioligand targeting the translocator protein (TSPO), does not produce a specific binding signal in approximately 14% of healthy volunteers. This phenomenon has not been reported for [11C]PK11195, another TSPO radioligand. We measured the specific binding signals with [3H]PK11195 and [3H]PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [3H]PBR28, although all samples showed [3H]PK11195 binding. There was a marked reduction in the affinity of [3H]PBR28 for TSPO in samples with no visible [3H]PBR28 autoradiographic signal ( K i=188±15.6 nmol/L), relative to those showing normal signal ( K i=3.4±0.5 nmol/L, P<0.001). Of this latter group, [3H]PBR28 bound with a two-site fit in 40% of cases, with affinities ( K i) of 4.0±2.4 nmol/L (high-affinity site) and 313±77 nmol/L (low-affinity site). There was no difference in Kd or Bmax for [3H]PK11195 in samples showing no [3H]PBR28 autoradiographic signal relative to those showing normal [3H]PBR28 autoradiographic signal. [3H]PK11195 bound with a single site for all samples. The existence of three different binding patterns with PBR28 (high-affinity binding (46%), low-affinity binding (23%), and two-site binding (31%)) suggests that a reduction in [11C]PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Two Binding Sites for [³H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

Owen

Howell

Tang

et al. 2010

J Cereb Blood Flow Metab

190

194

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“…At the carboxylic terminus, TSPO contains a cholesterol recognition amino acid consensus (CRAC) sequence [8]. Cholesterol binds with nanomolar affinity to this sequence [9], but the direct role of TSPO in steroidogenesis is under debate [10].…”

Section: Introductionmentioning

confidence: 99%

Structural Integrity of the A147T Polymorph of Mammalian TSPO

Jaremko

Giller

et al. 2015

ChemBioChem

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Ligands of the transmembrane protein TSPO are used for imaging of brain inflammation, but a common polymorphism in TSPO complicates their application to humans. Here we determined the three-dimensional structure and side chain dynamics of the A147T polymorph of mammalian TSPO in complex with the first-generation ligand PK11195. We show that A147T TSPO is able to retain the same structural and dynamic profile of the wild-type protein and thus binds PK11195 with comparable affinity. Our study is important for the design of more potent diagnostic and therapeutic ligands of TSPO.

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“…The PBR appears to be a heteromeric complex of at least three different subunits, viz., an isoquinoline binding subunit, a VDAC-voltage-dependent anion channel, and ANT-adenine nucleotide translocase [9][10][11]. Recent studies demonstrated that PBR is a high affinity cholesterol binding protein [12,13]. There are studies showing abundance of PBR in tumor cells and also specifically on nuclear membrane of tumor cells [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol

Verma

Chandra

2015

Ind J Clin Biochem

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Regulation of intracellular cholesterol homeostasis exists under balance between intracellular biosynthesis and uptake from extracellular origin by cell surface transport proteins. Expected role of cholesterol on either tumor suppressor gene and/or DNA synthesis has been aimed in the present study to explore intracellular cholesterol homeostasis in CLL subjects. Higher expressions of p53R2 (p53 dependent subunit of ribonucleotide reductase) and p53 were found in lymphocytes of chronic human lymphocytic leukemia as comparison to their normal counterparts. Inverse relation was found with p53 independent R2 subunit (in human hRRM2) of ribonucleotide reductase, which was found to be decreased from its control group. More expression of peripheral type benzodiazepine receptor, a cholesterol transporter, was noticed in isolated nuclear fraction with simultaneous increase of cholesterol concentration in cytoplasmic and nuclear compartments. A parallel increase of cholesterol in cell nucleus with increased p53R2 expression shows priority of the involvement of cholesterol in the process of cell replication.

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Structural and Functional Study of Reconstituted Peripheral Benzodiazepine Receptor

Cited by 155 publications

References 25 publications

Two Binding Sites for [³H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

Two Binding Sites for [³H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

Structural Integrity of the A147T Polymorph of Mammalian TSPO

Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol

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Structural and Functional Study of Reconstituted Peripheral Benzodiazepine Receptor

Cited by 155 publications

References 25 publications

Two Binding Sites for [3H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

Two Binding Sites for [3H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

Structural Integrity of the A147T Polymorph of Mammalian TSPO

Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol

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Product

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Two Binding Sites for [³H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation

Two Binding Sites for [³H]PBR28 in Human Brain: Implications for TSPO PET Imaging of Neuroinflammation