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

The Biochemical Journal
David R OwenVassilios Papadopoulos

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 fo...Continue Reading

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Citations

Jun 8, 2018·International Journal of Molecular Sciences·Frederick Bonsack, Sangeetha Sukumari-Ramesh
May 15, 2018·Endocrinology·Jinjiang FanVassilios Papadopoulos
May 3, 2018·Biology of Reproduction·Vimal SelvarajBarbara J Clark
Jul 14, 2018·Journal of Neurochemistry·Stefano MelettiGiuseppe Biagini
Mar 8, 2018·The Biochemical Journal·Barbara CostaClaudia Martini
Mar 25, 2019·International Journal of Molecular Sciences·Soria Iatmanen-HarbiJean-Jacques Lacapere
Feb 27, 2020·Journal of the Endocrine Society·Jinjiang FanVassilios Papadopoulos
Mar 23, 2018·Biology of Reproduction·Barry R Zirkin, Vassilios Papadopoulos
Aug 15, 2020·Frontiers in Endocrinology·Vimal SelvarajDouglas M Stocco
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Sep 5, 2019·Frontiers in Immunology·Khalid RashidThomas Langmann
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Jan 2, 2021·International Journal of Molecular Sciences·Jinjiang Fan, Vassilios Papadopoulos
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Aug 4, 2021·Biology of Reproduction·Wei Yan
Dec 23, 2019·Trends in Pharmacological Sciences·Jean-Jacques LacapereVassilios Papadopoulos
Nov 17, 2021·European Journal of Nuclear Medicine and Molecular Imaging·Sang Hee LeeSang Eun Kim

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Methods Mentioned

BETA
PCR
PCRs
scintillation spectrometry
NMR
contraception
Genotyping
Assay
confocal microscopy

Software Mentioned

AutoDock Vina
GraphPad
Prism
ImageJ
SAS

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