Translocator protein

Translocator protein (TSPO) is an 18 is_associated_with::kDa protein mainly found on the is_associated_with::outer mitochondrial membrane. It interacts with StAR (is_associated_with::steroidogenic acute regulatory protein) to transport is_associated_with::cholesterol into is_associated_with::mitochondria. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for is_associated_with::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 is_associated_with::gene. It belongs to family of is_associated_with::tryptophan-rich sensory proteins.

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

Cholesterol transport
TSPO binds with high affinity to is_associated_with::cholesterol and may transport it across the mitochondrial membrane to stimulate steroid synthesis in relevant tissues. However, a specific deletion of TSPO in steroidogenic is_associated_with::Leydig cells did not impair their synthesis of is_associated_with::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.

Immunomodulation
PBRs have many actions on immune cells including modulation of oxidative bursts by is_associated_with::neutrophils and is_associated_with::macrophages, inhibition of the proliferation of lymphoid cells and secretion of cytokines by is_associated_with::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.

Apoptosis
Ligands of TSPO have been shown to induce is_associated_with::apoptosis in human colorectal cancer cells. In lymphatic tissues, TSPO modulates apoptosis of thymocytes via reduction of mitochondrial transmembrane potential.

Stress adaptation
TSPO in the basal is_associated_with::land plant is_associated_with::Physcomitrella patens, a is_associated_with::moss, is essential for is_associated_with::adaptation to salt stress.

Tissue distribution
TSPO is found in many regions of the body including the human iris/is_associated_with::ciliary-body. Other tissues include the is_associated_with::heart, is_associated_with::liver, is_associated_with::adrenal and is_associated_with::testis, as well as is_associated_with::hemopoietic and is_associated_with::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 is_associated_with::plasma membrane.

Therapeutic applications
TSPO has been shown to be involved in a number of processes such as is_associated_with::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 is_associated_with::neuroactive steroids such as is_associated_with::allopregnanolone in the brain. This would make some TSPO ligands such as is_associated_with::emapunil (XBD-173) useful as potential is_associated_with::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 is_associated_with::USC Davis School of Gerontology showed that TSPO ligands can prevent and at least partially correct abnormalities present in a mouse model of is_associated_with::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 monomeric.

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.

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

Agonists

 * is_associated_with::YL-IPA08
 * is_associated_with::Ro5-4864 - original ligand with which TSPO receptor was characterised, now less used due to inter-species differences in binding affinity. Sedative yet also is_associated_with::convulsant and is_associated_with::anxiogenic in mice.


 * Peptides
 * 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


 * Non-peptides
 * is_associated_with::Alpidem
 * is_associated_with::Etifoxine
 * is_associated_with::DAA-1097
 * is_associated_with::DAA-1106
 * is_associated_with::DPA-713
 * is_associated_with::DPA-714
 * is_associated_with::Emapunil
 * is_associated_with::FGIN-127
 * is_associated_with::FGIN-143
 * is_associated_with::SSR-180,575

Antagonists

 * is_associated_with::PK-11195 - potent and selective antagonist for both rat and human forms of TSPO.