Owen, DR;
Fan, J;
Campioli, E;
Venugopal, S;
Midzak, A;
Daly, E;
Harlay, A;
... Papadopoulos, V; + view all
(2017)
TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis.
Biochemical Journal
, 474
(23)
pp. 3985-3999.
10.1042/BCJ20170648.
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Abstract
The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.
| Type: | Article |
|---|---|
| Title: | TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1042/BCJ20170648 |
| Publisher version: | http://doi.org/10.1042/BCJ20170648 |
| Language: | English |
| Additional information: | © 2017 The Author(s) This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY). |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, TRANSLOCATOR PROTEIN TSPO, PERIPHERAL BENZODIAZEPINE-RECEPTOR, LEYDIG TUMOR-CELLS, 18 KDA, PSYCHIATRIC-DISORDERS, TARGETED DISRUPTION, ADRENAL-CORTEX, SWISS-MODEL, BINDING, MICE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > IoN Central Administration |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10042663 |
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