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TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis

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 co...

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Autores principales: Owen, David R., Fan, Jinjiang, Campioli, Enrico, Venugopal, Sathvika, Midzak, Andrew, Daly, Edward, Harlay, Aline, Issop, Leeyah, Libri, Vincenzo, Kalogiannopoulou, Dimitra, Oliver, Eduardo, Gallego-Colon, Enrique, Colasanti, Alessandro, Huson, Les, Rabiner, Eugenii A., Suppiah, Puvan, Essagian, Charles, Matthews, Paul M., Papadopoulos, Vassilios
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697202/
https://www.ncbi.nlm.nih.gov/pubmed/29074640
http://dx.doi.org/10.1042/BCJ20170648
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author Owen, David R.
Fan, Jinjiang
Campioli, Enrico
Venugopal, Sathvika
Midzak, Andrew
Daly, Edward
Harlay, Aline
Issop, Leeyah
Libri, Vincenzo
Kalogiannopoulou, Dimitra
Oliver, Eduardo
Gallego-Colon, Enrique
Colasanti, Alessandro
Huson, Les
Rabiner, Eugenii A.
Suppiah, Puvan
Essagian, Charles
Matthews, Paul M.
Papadopoulos, Vassilios
author_facet Owen, David R.
Fan, Jinjiang
Campioli, Enrico
Venugopal, Sathvika
Midzak, Andrew
Daly, Edward
Harlay, Aline
Issop, Leeyah
Libri, Vincenzo
Kalogiannopoulou, Dimitra
Oliver, Eduardo
Gallego-Colon, Enrique
Colasanti, Alessandro
Huson, Les
Rabiner, Eugenii A.
Suppiah, Puvan
Essagian, Charles
Matthews, Paul M.
Papadopoulos, Vassilios
author_sort Owen, David R.
collection PubMed
description 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.
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spelling pubmed-56972022017-12-07 TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis Owen, David R. Fan, Jinjiang Campioli, Enrico Venugopal, Sathvika Midzak, Andrew Daly, Edward Harlay, Aline Issop, Leeyah Libri, Vincenzo Kalogiannopoulou, Dimitra Oliver, Eduardo Gallego-Colon, Enrique Colasanti, Alessandro Huson, Les Rabiner, Eugenii A. Suppiah, Puvan Essagian, Charles Matthews, Paul M. Papadopoulos, Vassilios Biochem J Research Articles 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. Portland Press Ltd. 2017-12-01 2017-11-21 /pmc/articles/PMC5697202/ /pubmed/29074640 http://dx.doi.org/10.1042/BCJ20170648 Text en © 2017 The Author(s) https://creativecommons.org/licenses/by/4.0/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) (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Articles
Owen, David R.
Fan, Jinjiang
Campioli, Enrico
Venugopal, Sathvika
Midzak, Andrew
Daly, Edward
Harlay, Aline
Issop, Leeyah
Libri, Vincenzo
Kalogiannopoulou, Dimitra
Oliver, Eduardo
Gallego-Colon, Enrique
Colasanti, Alessandro
Huson, Les
Rabiner, Eugenii A.
Suppiah, Puvan
Essagian, Charles
Matthews, Paul M.
Papadopoulos, Vassilios
TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
title TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
title_full TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
title_fullStr TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
title_full_unstemmed TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
title_short TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis
title_sort tspo mutations in rats and a human polymorphism impair the rate of steroid synthesis
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5697202/
https://www.ncbi.nlm.nih.gov/pubmed/29074640
http://dx.doi.org/10.1042/BCJ20170648
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