Translocator protein: pharmacology and steroidogenesis

Midzak, Andrew; Zirkin, Barry R.; Papadopoulos, Vassilios

doi:10.1042/bst20150061

Cited by 38 publications

(24 citation statements)

References 72 publications

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“…For the interested reader, we refer to the numerous reviews regarding TSPO research, which directly or indirectly approach this enigma (not only referred to in this study, but also in other studies). It is well known that TSPO may contribute to various functions, sometimes appearing without any commonality [64,65,66,67,68,69]. One may find that for some researchers, gene regulation via TSPO or by TSPO ligands may be an undesired side effect.…”

Section: Discussionmentioning

confidence: 99%

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Yasin

Veenman

Singh

et al. 2017

IJMS

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It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 min, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with real-time, reverse transcriptase (RT) PCR. At the time points of 15, 30, 45, and 60 min, as well as 3 and 24 h of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 h of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors.

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Section: Discussionmentioning

confidence: 99%

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Yasin

Veenman

Singh

et al. 2017

IJMS

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“…This conclusion has persisted for over two decades with a number of models having been proposed as to how TSPO functioned in cholesterol transport into the mitochondria. Several recent reviews summarize the current state of the role of TSPO in steroidogenesis (Aghazadeh et al, 2015, Midzak et al, 2015, Papadopoulos et al, 2015). …”

Section: The Peripheral Benzodiazepine Receptor (Pbr)/translocatormentioning

confidence: 99%

A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis

Stocco

Zhao

et al. 2017

Molecular and Cellular Endocrinology

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The synthesis of steroid hormones occurs in specific cells and tissues in the body in response to trophic hormones and other signals. In order to synthesize steroids de novo, cholesterol, the precursor of all steroid hormones, must be mobilized from cellular stores to the inner mitochondrial membrane (IMM) to be converted into the first steroid formed, pregnenolone. This delivery of cholesterol to the IMM is the rate-limiting step in this process, and has long been known to require the rapid synthesis of a new protein(s) in response to stimulation. Although several possibilities for this protein have arisen over the past few decades, most of the recent attention to fill this role has centered on the candidacies of the proteins the Translocator Protein (TSPO) and the Steroidogenic Acute Regulatory Protein (StAR). In this review, the process of regulating steroidogenesis is briefly described, the characteristics of the candidate proteins and the data supporting their candidacies summarized, and some recent findings that propose a serious challenge for the role of TSPO in this process are discussed.

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“…The neuroactive steroid biosynthetic pathway may be targeted at various levels in order to promote neurosteroidogenesis, including the 18 kDa translocator protein (TSPO), an outer mitochondrial membrane protein expressed at high levels in peripheral and CNS steroid‐producing cells . TSPO plays a key role in the rate‐limiting step of neuroactive steroid synthesis, consisting of cholesterol translocation into mitochondria in order to supply it to the cytochrome P450 enzyme CYP11A1 for conversion into pregnenolone, the precursor of all neurosteroids …”

Section: Figurementioning

confidence: 99%

“…[5] TSPO plays ak ey role in the rate-limiting step of neuroactive steroid synthesis, consistingo fc holesterol translocation into mitochondria in order to supply it to the cytochrome P450 enzyme CYP11A1 for conversion into pregnenolone, the precursor of all neurosteroids. [6] Numerous TSPO ligandsa re able to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells, and they have been proposed as innovative therapeutic tools in several pathological conditions, due to their neuroprotective, anxiolytic, anti-inflammatory,a nd regenerating properties in different in vitro andi nvivo models. [7][8][9][10] To date, phase II clinicalt rials have been concluded for the treatment of diabetic peripheral neuropathy (ClinicalTrials.gov identifier:Ta rgeting the biosyntheticp athway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligandsm ay be av iable therapeutic approachf or av ariety of neurodegenerativea nd neuropsychiatric diseases.…”

mentioning

confidence: 99%

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

et al. 2017

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Neuroactive steroids are endogenousn euromodulators that, by binding to membrane receptors and tuning gene expression via intracellular receptors, regulate many physiological functions. They can be synthesized in the brain de novo, so that they are termedn eurosteroids, or reach the central nervous system (CNS) from peripheral steroidogenico rgans,s uch as adrenals and gonads, and are locally metabolized. Neurosteroid levels are alteredi ns everal psychiatric and neurodegenerative diseases as ac onsequence of an impairment of neurosteroidogenesis;b oth preclinical and clinical studies emphasize atherapeutic potentialofn euroactive steroids for these diseases, whereby symptomatology ameliorates upon restoration of neuroactive steroid concentrations. [1][2][3] Neuroactive steroids exert potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly acting as positive allosteric modulators at specific sites on the a-subunit of the g-aminobutyric acid type Ar eceptor (GABA A R).[4] In addition, neuroactive steroids exert neuroprotective, neurotrophic, anti-inflammatory and anti-apoptotic activitiesi ns everala nimal modelso ft raumatic brain and spinal cord injury,c erebral ischemia, peripheraln europathy,a nd neurodegeneratived iseases (e.g.,A lzheimer's and Parkinson's diseases,m ultiple sclerosis, etc.). [2] However,d irect administration of neuroactive steroids has several challenges, including short half-life,l ow bioavailability, poor aqueouss olubility,d evelopmento ft olerance, and undesired side effects such as sedationa nd memory impairment that limit their therapeutic use. Consequently,m odulation of neurosteroidogenesis to restoret he alterede ndogenous neuroactive steroidt one may be ab etter therapeutic approach. [1][2][3] The neuroactive steroidb iosynthetic pathway may be targeted at variousl evels in order to promote neurosteroidogenesis, [3] including the 18 kDat ranslocator protein (TSPO), an outer mitochondrial membrane protein expressed at high levels in peripheral and CNS steroid-producing cells.[5] TSPO plays ak ey role in the rate-limiting step of neuroactive steroid synthesis, consistingo fc holesterol translocation into mitochondria in order to supply it to the cytochrome P450 enzyme CYP11A1 for conversion into pregnenolone, the precursor of all neurosteroids. [6] Numerous TSPO ligandsa re able to potently and dose-dependently stimulate steroid biosynthesis in steroidogenic cells, and they have been proposed as innovative therapeutic tools in several pathological conditions, due to their neuroprotective, anxiolytic, anti-inflammatory,a nd regenerating properties in different in vitro andi nvivo models. [7][8][9][10] To date, phase II clinicalt rials have been concluded for the treatment of diabetic peripheral neuropathy (ClinicalTrials.gov identifier:Ta rgeting the biosyntheticp athway of neuroactive steroids with specific 18 kDa translocator protein (TSPO) ligandsm ay be av iable therapeutic approachf or av ariety of neurodegenerativea nd neuropsychiatri...

show abstract

Translocator protein: pharmacology and steroidogenesis

Cited by 38 publications

References 72 publications

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

Classical and Novel TSPO Ligands for the Mitochondrial TSPO Can Modulate Nuclear Gene Expression: Implications for Mitochondrial Retrograde Signaling

A brief history of the search for the protein(s) involved in the acute regulation of steroidogenesis

Residence Time, a New parameter to Predict Neurosteroidogenic Efficacy of Translocator Protein (TSPO) Ligands: the Case Study of N,N‐Dialkyl‐2‐arylindol‐3‐ylglyoxylamides

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