scholarly journals Minireview: Translocator Protein (TSPO) and Steroidogenesis: A Reappraisal

2015 ◽  
Vol 29 (4) ◽  
pp. 490-501 ◽  
Author(s):  
Vimal Selvaraj ◽  
Douglas M. Stocco ◽  
Lan N. Tu
Keyword(s):  
Positive Impact ◽  
Transmembrane Protein ◽  
Steroid Hormone ◽  
Benzodiazepine Receptor ◽  
Translocator Protein ◽  
Research Progress ◽  
Peripheral Benzodiazepine Receptor ◽  
Hormone Production ◽  
Recent Developments ◽  
Mitochondrial Cholesterol

Abstract The 18-kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor, is a transmembrane protein in the outer mitochondrial membrane. TSPO has long been described as being indispensable for mitochondrial cholesterol import that is essential for steroid hormone production. In contrast to this initial proposition, recent experiments reexamining TSPO function have demonstrated that it is not involved in steroidogenesis. This fundamental change has forced a reexamination of the functional interpretations made for TSPO that broadly impacts both basic and clinical research across multiple fields. In this minireview, we recapitulate the key studies from 25 years of TSPO research and concurrently examine their limitations that perhaps led towards the incorrect association of TSPO and steroid hormone production. Although this shift in understanding raises new questions regarding the molecular function of TSPO, these recent developments are poised to have a significant positive impact for research progress in steroid endocrinology.

Guwiyang Wurra–‘Fire Mouse’: a global gene knockout model for TSPO/PBR drug development, loss-of-function and mechanisms of compensation studies

2015 ◽  
Vol 43 (4) ◽  
pp. 553-558 ◽  
Author(s):  
Ryan J. Middleton ◽  
Guo-Jun Liu ◽  
Richard B. Banati
Keyword(s):  
Mitochondrial Permeability Transition ◽  
Gene Knockout ◽  
Physiological Role ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Benzodiazepine Receptor ◽  
Translocator Protein ◽  
Loss Of Function ◽  
Recent Developments

The highly conserved 18-kDa translocator protein (TSPO) or peripheral benzodiazepine receptor (PBR), is being investigated as a diagnostic and therapeutic target for disease conditions ranging from inflammation to neurodegeneration and behavioural illnesses. Many functions have been attributed to TSPO/PBR including a role in the mitochondrial permeability transition pore (MPTP), steroidogenesis and energy metabolism. In this review, we detail the recent developments in determining the physiological role of TSPO/PBR, specifically based on data obtained from the recently generated Tspo knockout mouse models. In addition to defining the role of TSPO/PBR, we also describe the value of Tspo knockout mice in determining the selectivity, specificity and presence of any off-target effects of TSPO/PBR ligands.

scholarly journals Structure of the mammalian TSPO/PBR protein

2015 ◽  
Vol 43 (4) ◽  
pp. 566-571 ◽  
Author(s):  
Mariusz Jaremko ◽  
Łukasz Jaremko ◽  
Garima Jaipuria ◽  
Stefan Becker ◽  
Markus Zweckstetter
Keyword(s):  
Binding Site ◽  
Structural Properties ◽  
3D Structure ◽  
Benzodiazepine Receptor ◽  
Atomic Level ◽  
Translocator Protein ◽  
Peripheral Benzodiazepine Receptor ◽  
Pathological Conditions ◽  
First Time ◽  
Insight Into

The 3D structure of the 18-kDa transmembrane (TM) protein TSPO (translocator protein)/PBR (peripheral benzodiazepine receptor), which contains a binding site for benzodiazepines, is important to better understand its function and regulation by endogenous and synthetic ligands. We have recently determined the structure of mammalian TSPO/PBR in complex with the diagnostic ligand PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; Jaremko et al. (2014) Science 343, 1363–1366], providing for the first time atomic-level insight into the conformation of this protein, which is up-regulated in various pathological conditions including Alzheimer's disease and Parkinson's disease. Here, we review the studies which have probed the structural properties of mammalian TSPO/PBR as well as the homologues bacterial tryptophan-rich sensory proteins (TspOs) over the years and provide detailed insight into the 3D structure of mouse TSPO (mTSPO)/PBR in complex with PK11195.

scholarly journals Current status and future perspectives: TSPO in steroid neuroendocrinology

2016 ◽  
Vol 231 (1) ◽  
pp. R1-R30 ◽  
Author(s):  
Vimal Selvaraj ◽  
Lan N Tu
Keyword(s):  
Therapeutic Target ◽  
De Novo ◽  
Benzodiazepine Receptor ◽  
Translocator Protein ◽  
Current Status ◽  
Hormone Production ◽  
Neuronal Disease ◽  
Negative Impacts

The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPO-binding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

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