Translocator protein

Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. 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.^[1] In humans, the translocator protein is encoded by the TSPO gene.^[2][3]

Function

TSPO has many proposed functions,^[4] the most studied of these are:

• Cholesterol transport: TSPO binds with high affinity to cholesterol and transports it across the mitochondrial membrane where it is used in steroid synthesis.^[5]
• Immunomodulation: Expression of TSPO has been linked to inflammatory responses that occur after ischemia-reperfusion injury, following brain injury, and in some neurodegenerative diseases.
• Apoptosis: Ligands of TSPO have been shown to induce apoptosis in human colorectal cancer cells.
• Stress adaptation: TSPO in the basal land plant Physcomitrella patens, a moss, is essential for adaptation to salt stress.^[6]

An indicator of the importance of TSPO is that disruption of the gene in mice results in embryonic death.^[5]

Tissue distribution

Peripheral benzodiazepine receptors are found in many regions of the body including the human iris/ciliary-body.^[7] Other tissues where peripheral benzodiazepine receptors are found include the heart, liver, adrenal and testis, as well as hemopoietic and lymphatic cells.^[8] In lymphatic tissues, they modulate apoptosis of thymocytes via reduction of mitochondrial transmembrane potential.^[9] PBRs have many other 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.^[10] "Peripheral" benzodiazepine receptors are also found in the brain, although only at around a quarter the expression levels of the "central" benzodiazepine receptors.^[11]

Therapeutic Applications

TSPO has been shown to be involved in a number of processes such as inflammation,^[12] and TSPO ligands may be useful anti-cancer drugs.^[13][14] Activation of TSPO is also required for steroidogenesis to take place,^[15][16] and this is particularly important for the production of neuroactive steroids such as allopregnanolone in the brain. This makes some TSPO ligands such as emapunil (XBD-173) useful as potential anxiolytics which may have less side effects than traditional benzodiazepine-type drugs.^{[17][18][19][20]}

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.^[21]

Selective Ligands

Agonists

Peptides

• Anthralin - 16kDa polypeptide, binds to both TSPO receptor and dihydropyridine-sensitive calcium channels with high affinity.^[22]
• Diazepam binding inhibitor (DBI) - 11kDa neuropeptide, potent agonist for TSPO receptor and stimulates steroidogenesis in vivo,^[5][23][24] also negative allosteric modulator of benzodiazepine-sensitive GABA_A receptors.^[25]
• DBI 17-50 fragment - active processing product of DBI

Non-peptides

• DAA-1097
• DAA-1106
• Emapunil
• FGIN-127
• FGIN-143
• SSR-180,575

Antagonists

• 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.^[26]

References

External links

• MeSH TSPO+protein,+human