mutations in rats and a human polymorphism impair the rate of steroid synthesis.
Title | mutations in rats and a human polymorphism impair the rate of steroid synthesis. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Owen, D. R., Fan J., Campioli E., Venugopal S., Midzak A., Daly E., Harlay A., Issop L., Libri V., Kalogiannopoulou D., Oliver E., Gallego-Colon E., Colasanti A., Huson L., Rabiner E. A., Suppiah P., Essagian C., Matthews P. M., & Papadopoulos V. |
Journal | Biochem J |
Volume | 474 |
Issue | 23 |
Pagination | 3985-3999 |
Date Published | 2017 11 21 |
ISSN | 1470-8728 |
Keywords | Adolescent, Adrenocorticotropic Hormone, Adult, Animals, Base Sequence, Carrier Proteins, Cholesterol Esters, Chorionic Gonadotropin, Cloning, Molecular, Corticosterone, Embryo, Mammalian, Escherichia coli, Gene Expression, Humans, Hydrocortisone, Male, Plasmids, Polymorphism, Single Nucleotide, Pregnanolone, Rats, Rats, Transgenic, Receptors, GABA, Receptors, GABA-A, Recombinant Proteins, Testosterone, Zinc Fingers, Zygote |
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 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 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. |
DOI | 10.1042/BCJ20170648 |
Alternate Journal | Biochem. J. |
PubMed ID | 29074640 |
PubMed Central ID | PMC5697202 |
Grant List | G0900897 / / Medical Research Council / United Kingdom MOP125983 / / CIHR / Canada PJT148659 / / CIHR / Canada MR/N008219/1 / / Medical Research Council / United Kingdom |