|Translocator protein (18kDa)|
|Symbols||; BPBS; BZRP; DBI; IBP; MBR; PBR; PBS; PKBS; PTBR; mDRC; pk18|
|External IDs||ChEMBL: GeneCards:|
Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It interacts with StAR (steroidogenic acute regulatory protein) to transport cholesterol into mitochondria. 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. In humans, the translocator protein is encoded by the TSPO gene. It belongs to family of tryptophan-rich sensory proteins.
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. The most studied of these include roles in the immune response, steroid synthesis and apoptosis.
TSPO binds with high affinity to cholesterol and may transport it across the mitochondrial membrane to stimulate steroid synthesis in relevant tissues. However, a specific deletion of TSPO in steroidogenic Leydig cells did not impair their synthesis of testosterone. Thus, a role for TSPO in steroid production is 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. 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.
PBRs have many actions on immune cells including modulation of oxidative bursts by neutrophils and macrophages, and inhibition of macrophage secretion of cytokines inhibition of the proliferation of lymphoid cells and secretion of cytokines by macrophages. Expression of TSPO is also linked to inflammatory responses that occur after ischemia-reperfusion injury, following brain injury, and in some neurodegenerative diseases.
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. Oxidative stress is a strong contributing factor to cardiovascular disease, and often occurs because of inflammation caused by ischemia reperfusion injury. 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. 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.
Ligands of TSPO have been shown to induce apoptosis in human colorectal cancer cells. In lymphatic tissues, TSPO modulates apoptosis of thymocytes via reduction of mitochondrial transmembrane potential.
TSPO is found in many regions of the body including the human iris/ciliary-body. Other tissues include the heart, liver, adrenal and testis, as well as hemopoietic and lymphatic cells. "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.
TSPO has been shown to be involved in a number of processes such as inflammation, and TSPO ligands may be useful anti-cancer drugs. Activation of TSPO was considered by some to be required for the synthesis of steroids including neuroactive steroids such as allopregnanolone in the brain. This would make some TSPO ligands such as emapunil (XBD-173) useful as potential anxiolytics which may have less side effects than traditional benzodiazepine-type drugs. This role is definitively cast into doubt with later data showing TSPO is not required for steroid production.
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.
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. TSPO can be used as a biomarker to detect the presence and severity of inflammation in the heart and atherosclerotic plaques. Inhibiting the over-production of TSPO can lead to a reduced incidence of arrhythmias which are most often caused by ischemia reperfusion injury. 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. 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.
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 in the decrease in PK11195 binding (Fan et al., 2012).
The mammalian TSPO in a complex with diagnostic ligand is nomomeric.
L. Jaremko, M. Jaremko, K. Giller, S. Becker, M. Zweckstetter, Structure of the mitochondrial translocator protein in complex with a diagnostic ligand, Science, 343 (2014) 1363-1366.
J. Fan, P. Lindemann, M.G. Feuilloley, V. Papadopoulos, Structural and functional evolution of the translocator protein (18 kDa), Curr Mol Med, 12 (2012) 369-386.
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.
- Anthralin - 16kDa polypeptide, binds to both TSPO receptor and dihydropyridine-sensitive calcium channels with high affinity.
- Diazepam binding inhibitor (DBI) - 11kDa neuropeptide, potent agonist for TSPO receptor and stimulates steroidogenesis in vivo, also negative allosteric modulator of benzodiazepine-sensitive GABAA receptors.
- DBI 17-50 fragment - active processing product of DBI
- PK-11195 - potent and selective antagonist for both rat and human forms of TSPO.
- Ro5-4864 - original ligand with which TSPO receptor was characterised, now less used due to inter-species differences in binding affinity. Sedative yet also convulsant and anxiogenic in mice.
- Papadopoulos V, Baraldi M, Guilarte TR, Knudsen TB, Lacapère JJ, Lindemann P, Norenberg MD, Nutt D, Weizman A, Zhang MR, Gavish M (August 2006). "Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function". Trends Pharmacol. Sci. 27 (8): 402–9. doi:10.1016/j.tips.2006.06.005. PMID 16822554.
- Chang YJ, McCabe RT, Rennert H, Budarf ML, Sayegh R, Emanuel BS, Skolnick P, Strauss JF (1992). "The human "peripheral-type" benzodiazepine receptor: regional mapping of the gene and characterization of the receptor expressed from cDNA". DNA Cell Biol. 11 (6): 471–80. doi:10.1089/dna.1992.11.471. PMID 1326278.
- Riond J, Mattei MG, Kaghad M, Dumont X, Guillemot JC, Le Fur G, Caput D, Ferrara P (January 1991). "Molecular cloning and chromosomal localization of a human peripheral-type benzodiazepine receptor". Eur. J. Biochem. 195 (2): 305–11. doi:10.1111/j.1432-1033.1991.tb15707.x. PMID 1847678.
- Casellas P, Galiegue S, Basile AS (2002). "Peripheral benzodiazepine receptors and mitochondrial function". Neurochem Int 40 (6): 475–86. doi:10.1016/S0197-0186(01)00118-8. PMID 11850104.
- Papadopoulos V, Amri H, Boujrad N, Cascio C, Culty M, Garnier M, Hardwick M, Li H, Vidic B, Brown AS, Reversa JL, Bernassau JM, Drieu K (January 1997). "Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis". Steroids 62 (1): 21–8. doi:10.1016/S0039-128X(96)00154-7. PMID 9029710.
- Morohaku K, Pelton SH, Daugherty DJ, Ronald Butler W, Deng W, Selvaraj V (2013). "Translocator Protein/Peripheral Benzodiazepine Receptor Is Not Required for Steroid Hormone Biosynthesis". Endocrinology 155 (1): 89–97. doi:10.1210/en.2013-1556. PMID 24174323.
- Xiaolong, Q., Jiahong, X., Wang, F., and Junjie, X. (2012) Translocator Protein (18 kDa): A Promising Therapeutic Target and Diagnostic Tool for Cardiovascular Diseases. Oxid Med Cell Longev. 2012(1-9) Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516045/pdf/OXIMED2012-162934.pdf
- Fairweather, D. et al. (2014) Sex Differences in Translocator Protein 18 kDa (TSPO) in the Heart: Implications for Imaging Myocardial Inflammation. J. of Cardiovasc. Trans. Res. 7(192–202). Retrieved from: http://download.springer.com/static/pdf/955/art%253A10.1007%252Fs12265-013-9538-0.pdf?auth66=1393775645_ed2e5124742b1a0ce01235b2e9ae069c&ext=.pdf
- Pawlikowski M (1993). "Immunomodulating effects of peripherally acting benzodiazepines". New York: In Peripheral Benzodiazepine Receptors. Academic press. pp. 125–135.
- Batarseh, A., and Papadopoulos, V. ( 2011) Regulation of Translocator Protein 19 kDa (TSPO) Expression in Health and Disease States. Mol Cell Endocrinol.327(1-2). Retrieved from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2922062/pdf/nihms-218559.pdf
- Fairweather, D. et al. (2014) Sex Differemces in Translocator Protein 18 kDa (TSPO) in the Heart: Implications for Imaging Myocardial Inflammation. J. of Cardiovasc. Trans. Res. 7(192–202). Retrieved from: http://download.springer.com/static/pdf/955/art%253A10.1007%252Fs12265-013-9538-0.pdf?auth66=1393775645_ed2e5124742b1a0ce01235b2e9ae069c&ext=.pdf
- Tanimoto Y, Onishi Y, Sato Y, Kizaki H (February 1999). "Benzodiazepine receptor agonists modulate thymocyte apoptosis through reduction of the mitochondrial transmembrane potential". Jpn. J. Pharmacol. 79 (2): 177–83. doi:10.1254/jjp.79.177. PMID 10202853.
- Frank W, Baar KM, Qudeimat E, Woriedh M, Alawady A, Ratnadewi D, Gremillon L, Grimm B, Reski R (September 2007). "A mitochondrial protein homologous to the mammalian peripheral-type benzodiazepine receptor is essential for stress adaptation in plants". Plant J. 51 (6): 1004–18. doi:10.1111/j.1365-313X.2007.03198.x. PMID 17651369.
- Valtier D, Malgouris C, Gilbert JC, Guicheney P, Uzan A, Gueremy C, Le Fur G, Saraux H, Meyer P (June 1987). "Binding sites for a peripheral type benzodiazepine antagonist ([3H]PK 11195) in human iris". Neuropharmacology 26 (6): 549–52. doi:10.1016/0028-3908(87)90146-8. PMID 3037422.
- Woods MG, Williams DC (1996). Multiple forms and locations for the peripheral-type benzodiazepine receptor. Biochemical Pharmacology 52. pp. 1805–1814. doi:10.1016/S0006-2952(96)00558-8. PMID 8951338.
- Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R (July 1982). "Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864". Molecular Pharmacology 22 (1): 26–32. PMID 6289073.
- Chen MK, Guilarte TR (April 2008). "Translocator protein 18 kDa (TSPO): molecular sensor of brain injury and repair". Pharmacology & Therapeutics 118 (1): 1–17. doi:10.1016/j.pharmthera.2007.12.004. PMC 2453598. PMID 18374421.
- Santidrián AF, Cosialls AM, Coll-Mulet L, Iglesias-Serret D, de Frias M, González-Gironès DM, Campàs C, Domingo A, Pons G, Gil J (December 2007). "The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells". Haematologica 92 (12): 1631–8. doi:10.3324/haematol.11194. PMID 18055986.
- Kugler W, Veenman L, Shandalov Y, Leschiner S, Spanier I, Lakomek M, Gavish M (2008). "Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glioblastoma cells exposed to erucylphosphohomocholine". Cellular Oncology : the Official Journal of the International Society for Cellular Oncology 30 (5): 435–50. PMID 18791274.
- Veenman L, Papadopoulos V, Gavish M (2007). "Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response". Current Pharmaceutical Design 13 (23): 2385–405. doi:10.2174/138161207781368710. PMID 17692008.
- Falchi AM, Battetta B, Sanna F, Piludu M, Sogos V, Serra M, Melis M, Putzolu M, Diaz G (August 2007). "Intracellular cholesterol changes induced by translocator protein (18 kDa) TSPO/PBR ligands". Neuropharmacology 53 (2): 318–29. doi:10.1016/j.neuropharm.2007.05.016. PMID 17631921.
- Mealy NE, Bayés M, Lupone B (2006). "Psychiatric Disorders". Drugs of the Future 31 (3): 259.
- Da Settimo F, Simorini F, Taliani S, La Motta C, Marini AM, Salerno S, Bellandi M, Novellino E, Greco G, Cosimelli B, Da Pozzo E, Costa B, Simola N, Morelli M, Martini C (September 2008). "Anxiolytic-like effects of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides by modulation of translocator protein promoting neurosteroid biosynthesis". Journal of Medicinal Chemistry 51 (18): 5798–806. doi:10.1021/jm8003224. PMID 18729350.
- Taliani S, Da Settimo F, Da Pozzo E, Chelli B, Martini C (September 2009). "Translocator Protein Ligands as Promising Therapeutic Tools for Anxiety Disorders". Current Medicinal Chemistry 16 (26): 3359–80. doi:10.2174/092986709789057653. PMID 19548867.
- Rupprecht R, Rammes G, Eser D, Baghai TC, Schüle C, Nothdurfter C, Troxler T, Gentsch C, Kalkman HO, Chaperon F, Uzunov V, McAllister KH, Bertaina-Anglade V, La Rochelle CD, Tuerck D, Floesser A, Kiese B, Schumacher M, Landgraf R, Holsboer F, Kucher K (June 2009). "Translocator Protein (18 kD) as Target for Anxiolytics Without Benzodiazepine-Like Side Effects". Science 325 (5939): 490–3. doi:10.1126/science.1175055. PMID 19541954.
- Barron, A. M.; Garcia-Segura, L. M.; Caruso, D.; Jayaraman, A.; Lee, J. -W.; Melcangi, R. C.; Pike, C. J. (2013). "Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease". The Journal of Neuroscience 33 (20): 8891–8897. doi:10.1523/JNEUROSCI.1350-13.2013. PMID 23678130.
- Owen DR, Yeo AJ, Gunn RN, Song K, Wadsworth G, Lewis A, Rhodes C, Pulford DJ, Bennacef I, Parker CA, Stjean PL, Cardon LR, Mooser VE, Matthews PM, Rabiner EA, Rubio JP (October 2011). "An 18-kDa Translocator Protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28". J Cereb Blood Flow Metab 32 (1): 1–5. doi:10.1038/jcbfm.2011.147. PMC 3323305. PMID 22008728.
- Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Weisinger G, Weizman A (December 1999). "Enigma of the peripheral benzodiazepine receptor". Pharmacological Reviews 51 (4): 629–50. PMID 10581326.
- Costa E, Auta J, Guidotti A, Korneyev A, Romeo E (June 1994). "The pharmacology of neurosteroidogenesis". The Journal of Steroid Biochemistry and Molecular Biology 49 (4–6): 385–9. doi:10.1016/0960-0760(94)90284-4. PMID 8043504.
- Garnier M, Boujrad N, Ogwuegbu SO, Hudson JR, Papadopoulos V (September 1994). "The polypeptide diazepam-binding inhibitor and a higher affinity mitochondrial peripheral-type benzodiazepine receptor sustain constitutive steroidogenesis in the R2C Leydig tumor cell line". The Journal of Biological Chemistry 269 (35): 22105–12. PMID 8071335.
- Bormann J, Ferrero P, Guidotti A, Costa E (1985). "Neuropeptide modulation of GABA receptor C1- channels". Regulatory Peptides. Supplement 4: 33–8. doi:10.1016/0167-0115(85)90215-0. PMID 2414820.
- Pellow S, File SE (July 1984). "Behavioural actions of Ro 5-4864: a peripheral-type benzodiazepine?". Life Sciences 35 (3): 229–40. doi:10.1016/0024-3205(84)90106-1. PMID 6087055.