Translocator protein

Last updated
TSPO
Identifiers
Aliases TSPO , BPBS, BZRP, DBI, IBP, MBR, PBR, PBS, PKBS, PTBR, mDRC, pk18, translocator protein
External IDs OMIM: 109610 MGI: 88222 HomoloGene: 574 GeneCards: TSPO
Orthologs
SpeciesHumanMouse
Entrez

706

12257

Ensembl

ENSG00000100300

ENSMUSG00000041736

UniProt

P30536

P50637

RefSeq (mRNA)

NM_000714
NM_001256530
NM_001256531
NM_007311

NM_009775

RefSeq (protein)

NP_033905

Location (UCSC) Chr 22: 43.15 – 43.16 Mb Chr 15: 83.45 – 83.46 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. [5] It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. [6] In humans, the translocator protein is encoded by the TSPO gene. [7] [8] It belongs to a family of tryptophan-rich sensory proteins. Regarding intramitochondrial cholesterol transport, TSPO has been proposed to interact with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria, though evidence is mixed. [9]

Contents

Function

In animals, TSPO (PBR) is a mitochondrial protein usually located in the outer mitochondrial membrane and characterised by its ability to bind a variety of benzodiazepine-like drugs, as well as to dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway.

TSPO has many proposed functions depending on the tissue. [10] The most studied of these include roles in the immune response, steroid synthesis and apoptosis.

Cholesterol transport and bile acid biosynthesis

Mitochondrial cholesterol transport is a molecular function closely tied to TSPO in the scientific literature. TSPO binds with high affinity to the lipid cholesterol, and pharmacological ligands of TSPO facilitate cholesterol transport across the mitochondrial intermembrane space to stimulate steroid synthesis and bile acid synthesis in relevant tissues. [11] However, TSPO deletion in genetically engineered mouse models has yielded mixed results regarding the physiological necessity of TSPO's role in steroidogenesis. Deletion of TSPO in steroidogenic Leydig cells did not impair synthesis of the steroid testosterone. [12] Thus, though biochemical and pharmacological experimentation suggest an important role for TSPO in cellular cholesterol transport and steroid biosynthesis, [13] TSPO's necessity in this process remains controversial.

Regulation in the heart

TSPO (Translocator protein) acts to regulate heart rate and contractile force by its interaction with voltage-dependent calcium channels in cardiac myocytes. [14] The interaction between TSPO and calcium channels can alter cardiac action potential durations, thus contractility of the heart. In healthy individuals, TSPO has a cardio-protective role. When TSPO is up-regulated in the presence of infections, it can limit the inflammatory response, which can be cardio-damaging. [15]

Immunomodulation

PBRs (TSPOs) have many actions on immune cells including modulation of oxidative bursts by neutrophils and macrophages, inhibition of the proliferation of lymphoid cells and secretion of cytokines by macrophages. [16] [17] Expression of TSPO is also linked to inflammatory responses that occur after ischemia-reperfusion injury, following hemorrhagic brain injury, [18] and in some neurodegenerative diseases.[ citation needed ]

Increased expression of TSPO is linked to the inflammatory responses in the heart that may cause myocarditis, which can lead to myocardial necrosis. TSPO is present in mast cells and macrophages, indicating its role in the immune system. [14] Oxidative stress is a strong contributing factor to cardiovascular disease, and often occurs because of inflammation caused by ischemia reperfusion injury. [19] Coxsackievirus B3 (CVB3) causes immune cells CD11b+ (present on macrophages) to stimulate inflammatory infiltration. Functionally, CD11b+ regulates leukocyte adhesion and migration to regulate the inflammatory response. [15] Following infection, CD11b+ is up-regulated, activating these immune responses, which then activate an increased expression of TSPO. These immune cells can cause myocarditis which can progress to dilated cardiomyopathy and heart failure. [15]

Apoptosis

Ligands of TSPO have been shown to induce apoptosis in human colorectal cancer cells.[ citation needed ] In lymphatic tissues, TSPO modulates apoptosis of thymocytes via reduction of mitochondrial transmembrane potential. [20]

Stress adaptation

TSPO in the basal land plant Physcomitrella patens , a moss, is essential for adaptation to salt stress. [21]

Tissue distribution

TSPO is found in many regions of the body including the human iris/ciliary-body. [22] Other tissues include the heart, liver, adrenal and testis, as well as hemopoietic and lymphatic cells. [23] "Peripheral" benzodiazepine receptors are also found in the brain, although only at around a quarter the expression levels of the "central" benzodiazepine receptors located at the plasma membrane. [24]

Therapeutic applications

TSPO has been shown to be involved in a number of processes such as inflammation, [16] [25] and TSPO ligands may be useful anti-cancer drugs. [26] [27]

Pharmacological activation of TSPO has been observed to be a potent stimulator of steroid biosynthesis [28] [29] including neuroactive steroids such as allopregnanolone in the brain, which exert anxiolytic properties. [30] Thus, TSPO ligands such as emapunil, alpidem, and etifoxine have been proposed to be useful as potential anxiolytics which may have less addiction-based side effects than traditional benzodiazepine-type drugs., [31] [32] [33] [34] though toxicity side-effects remain a significant barrier in drug development. [35]

A 2013 study led by researchers from USC Davis School of Gerontology showed that TSPO ligands can prevent and at least partially correct abnormalities present in a mouse model of Alzheimer's disease. [36]

TSPO as a biomarker is a newly discovered non-invasive procedure, and has also been linked as a biomarker for other cardiovascular related diseases including: myocardial infarction (due to ischemic reperfusion), cardiac hypertrophy, atherosclerosis, arrhythmias, and large vessel vasculitis. [19] TSPO can be used as a biomarker to detect the presence and severity of inflammation in the heart and atherosclerotic plaques. [15] Inhibiting the over-production of TSPO can lead to a reduced incidence of arrhythmias which are most often caused by ischemia reperfusion injury. [19] TSPO ligands are used as a therapy after ischemia reperfusion injury to preserve the action potentials in cardiac tissue and restore normal electrical activity of the heart. [14] Higher levels of TSPO are present in those with heart disease, a change that is more common in men than women because testosterone worsens the inflammation causing permanent damage to the heart. [15]

The first high-resolution 3D solution structure of mammalian (mouse) translocator protein (TSPO) in a complex with its diagnostic PK11195 ligand was determined by means of NMR spectroscopy techniques by scientists from the Max-Planck Institute for Biophysical Chemistry in Goettingen in Germany in March 2014 (Jaremko et al., 2014) and has a PDB id: 2MGY. Obtained high-resolution clearly confirms a helical character of a protein and its complex with a diagnostic ligand in solution. The 3D structure of the mTSPO-PK11195 complex comprises five transmembrane α-helices (TM1 to TM5) that tightly pack together in the clockwise order TM1-TM2-TM5-TM4-TM3 (cytosol view). The mammalian TSPO in a complex with diagnostic ligand is nomomeric. The loop located in between TM1 and TM2 helices closes the entrance to the space between helices in which are bound with PK11195 molecule. Site-directed mutagenesis studies of mTSPO revealed that region important for PK11195 binding comprise amino acids from 41 to 51, because the deletion of this region resulted in the decrease in PK11195 binding (Fan et al., 2012).

The mammalian TSPO in a complex with the diagnostic ligand PK11195 is monomeric. [37] [38]

Imaging

Ligands of the TSPO are very useful for imaging of inflammation. For example, the radioligand [3H]PK-11195 has been used in receptor autoradiography to study neuroinflammation following brain injury. The affinity of [11C]PBR28 depends on a single polymorphism (rs6971) in the TSPO gene. [39]

Measuring microglial activation in vivo is possible using PET imaging and radioligands binding to 18 kDa translocator protein (TSPO). [40] Activation can be measured using the PET tracer (R)-[11C]PK11195 and others like PBR28 are under research. [41]

Ligands

TSPO ligands [5] (endogenous or synthetic) modulate the action of this receptor, activating the transport of cholesterol from the outer to the inner mitochondrial membrane.

Agonists

Peptides
Non-peptides

Antagonists

See also

Related Research Articles

<span class="mw-page-title-main">Neurosteroid</span> Compounds that affect neuronal excitability through modulation of specific ionotropic receptors

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain. The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function. The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy and traumatic brain injury. Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.

<span class="mw-page-title-main">Alpidem</span> Anxiolytic medication

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was discontinued due to liver toxicity. Alpidem is taken by mouth.

The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.

<span class="mw-page-title-main">Cholesterol side-chain cleavage enzyme</span> Mammalian protein found in Homo sapiens

Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an acronym for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reaction in the process of steroidogenesis in all mammalian tissues that specialize in the production of various steroid hormones.

<span class="mw-page-title-main">PK-11195</span> Chemical compound

PK-11195 is an isoquinoline carboxamide which binds selectively to the peripheral benzodiazepine receptor (PBR). It is one of the most commonly used PBR ligands due to its high affinity for the PBR in all species, although it is starting to be replaced by newer and more selective ligands.

<span class="mw-page-title-main">Etifoxine</span> Anxiolytic medication

Etifoxine, sold under the trade name Stresam among others, is a nonbenzodiazepine anxiolytic agent, primarily indicated for short-term management of adjustment disorder, specifically instances of situational depression accompanied by anxiety, such as stress-induced anxiety. Administration is by mouth. Side effects associated with etifoxine use include slight drowsiness, headache, skin eruptions, and allergic reactions. In rare cases, etifoxine has been linked to severe skin and liver toxicity, as well as menstrual bleeding between periods. Unlike benzodiazepines, etifoxine does not cause sedation or lack of coordination. Etifoxine acts as a GABAA receptor positive allosteric modulator and as a ligand for translocator proteins. Both mechanisms are conjectured to contribute to its anxiolytic properties.

<span class="mw-page-title-main">Estrogen-related receptor alpha</span> Protein-coding gene in the species Homo sapiens

Estrogen-related receptor alpha (ERRα), also known as NR3B1, is a nuclear receptor that in humans is encoded by the ESRRA gene. ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha, but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα. Currently, ERRα is considered an orphan nuclear receptor.

<span class="mw-page-title-main">Diazepam binding inhibitor</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA-binding protein in humans belongs to the family of Acyl-CoA-binding proteins.

<span class="mw-page-title-main">Emapunil</span> Chemical compound

Emapunil is an anxiolytic drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. This protein has multiple functions, among which is regulation of steroidogenesis, particularly the production of neuroactive steroids such as allopregnanolone in the brain. In both animal and human trials, emapunil produced fast acting anxiolytic and anti-panic effects, without producing sedation or withdrawal symptoms following cessation of use. Emapunil is also used in its 11C radiolabelled form to map the distribution of TSPO receptors in the brain.

<span class="mw-page-title-main">FGIN-127</span> Chemical compound

FGIN-1-27 is an anxiolytic drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. It is thought to produce anxiolytic effects by stimulating steroidogenesis of neuroactive steroids such as allopregnanolone.

<span class="mw-page-title-main">FGIN-143</span> Chemical compound

FGIN-1-43 is an anxiolytic drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. It is thought to produce anxiolytic effects by stimulating steroidogenesis of neuroactive steroids such as allopregnanolone, and is several times more potent than the related drug FGIN-127.

<span class="mw-page-title-main">SSR-180,575</span> Chemical compound

SSR-180,575 is a drug which acts as a selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO. It has been shown to have neuroprotective and cardioprotective effects and to stimulate steroidogenesis of pregnenolone in the brain, which may be linked to its neuroprotective action.

<span class="mw-page-title-main">DAA-1097</span> Chemical compound

DAA-1097 is a drug which acts as a potent and selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO, but with no affinity at central benzodiazepine receptors. It has anxiolytic effects in animal studies.

<span class="mw-page-title-main">DAA-1106</span> Chemical compound

DAA-1106 is a drug which acts as a potent and selective agonist at the peripheral benzodiazepine receptor, also known as the mitochondrial 18 kDa translocator protein or TSPO, but with no affinity at the GABAA receptor. It has anxiolytic effects in animal studies. DAA-1106 has a sub-nanomolar binding affinity (Ki) of 0.28nM, and has been used extensively in its 3H or 11C radiolabelled form to map TSPO in the body and brain, which has proved especially helpful in monitoring the progress of neurodegenerative diseases such as Alzheimer's disease.

<span class="mw-page-title-main">Ro5-4864</span> Chemical compound

Ro5-4864 (4'-chlorodiazepam) is a drug which is a benzodiazepine derivative of diazepam. However unlike most benzodiazepine derivatives, Ro5-4864 lacks affinity for GABAA receptors and lacks typical benzodiazepine effects, instead being sedative yet also convulsant and anxiogenic in effects. Ro5-4864 was found to be a potent ligand for the "peripheral benzodiazepine receptor", later renamed to mitochondrial translocator protein 18kDa (TSPO). Despite its convulsant effects, at lower doses Ro5-4864 has proved to be neuroprotective and has become widely used for research into the role of the TSPO protein in neurotoxicity. In vitro studies and rodent models also suggest the possibility of analgesic, antidepressant, cardioprotective, and anti-cancer effects.

Tryptophan-rich sensory proteins (TspO) are a family of proteins that are involved in transmembrane signalling. In either prokaryotes or mitochondria they are localized to the outer membrane, and have been shown to bind and transport dicarboxylic tetrapyrrole intermediates of the haem biosynthetic pathway. They are associated with the major outer membrane porins and with the voltage-dependent anion channel.

<span class="mw-page-title-main">DPA-714</span> Chemical compound

DPA-714 or N,N-diethyl-2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide is a selective ligand for the translocator protein (TSPO) currently under evaluation for several clinical applications. For this reason, a practical, multigram synthetic route for its preparation has been described.

<span class="mw-page-title-main">DPA-713</span> Chemical compound

DPA-713 or N,N-diethyl-2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide is a selective ligand for the translocator protein (TSPO).

A neurosteroidogenesis inhibitor is a drug that inhibits the production of endogenous neurosteroids. Neurosteroids include the excitatory neurosteroids pregnenolone sulfate, dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEA-S), and the inhibitory neurosteroids allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol, among others. By inhibiting the synthesis of endogenous neurosteroids, neurosteroidogenesis inhibitors have effects in the central nervous system.

<span class="mw-page-title-main">Vassilios Papadopoulos</span>

Vassilios Papadopoulos, DPharm, PhD, DSc (hon), born February 18, 1961, in Athens, Greece, is a scholar, researcher, inventor, professor, and university administrator who has served as dean of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences at the University of Southern California in Los Angeles, California since 2016. Previously, he was the associate vice president and director of the Biomedical Graduate Research Organization at Georgetown University from 2005 to 2007, and the executive director and chief scientific officer of the Research Institute of the McGill University Health Center from 2007 to 2015.

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