title: Translocator protein-mediated pharmacology of cholesterol transport and steroidogenesis.
abstract: Steroidogenesis begins with cholesterol transfer into mitochondria through the transduceosome, a complex composed of cytosolic proteins that include steroidogenesis acute regulatory protein (STAR), 14-3-3 adaptor proteins, and the outer mitochondrial membrane proteins Translocator Protein (TSPO) and Voltage-Dependent Anion Channel (VDAC). TSPO is a drug- and cholesterol-binding protein found at particularly high levels in steroid synthesizing cells. Its aberrant expression has been linked to cancer, neurodegeneration, neuropsychiatric disorders and primary hypogonadism. Brain steroids serve as local regulators of neural development and excitability. Reduced levels of these steroids have been linked to depression, anxiety and neurodegeneration. Reduced serum testosterone is common among subfertile young men and aging men, and is associated with depression, metabolic syndrome and reduced sexual function. Although testosterone-replacement therapy is available, there are undesired side-effects. TSPO drug ligands have been proposed as therapeutic agents to regulate steroid levels in the brain and testis.
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Department of Pharmacology & Therapeutics, McGill University, Montreal, Quebec, Canada; Departments of Biochemistry, McGill University, Montreal, Quebec, Canada. Electronic address: vassilios.papadopoulos@mcgill.ca.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Yasaman
authors.initials: Y
authors.lastname: Aghazadeh
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Fan
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada.
authors.forename: Enrico
authors.initials: E
authors.lastname: Campioli
authors.affiliation: Department of Biochemistry and Molecular Biology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Zirkin
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada; Departments of Biochemistry, McGill University, Montreal, Quebec, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Midzak
mesh_terms: D000818:Animals; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D018079:Receptors, GABA / Q000378:metabolism*; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D018079:Receptors, GABA; D013256:Steroids; D002784:Cholesterol
keywords: Adrenal; Brain; Gonads; Pharmacology; Steroidogenesis; TSPO
references.citation: Am J Psychiatry. 1998 Jul;155(7):910-3
references.pmid: 9659856
references.citation: Endocrinology. 1998 Dec;139(12):4991-7
references.pmid: 9832438
references.citation: Biol Psychiatry. 1999 Feb 1;45(3):274-7
references.pmid: 10023501
references.citation: J Steroid Biochem Mol Biol. 1999 Apr-Jun;69(1-6):123-30
references.pmid: 10418986
references.citation: Endocr Rev. 2004 Dec;25(6):947-70
references.pmid: 15583024
references.citation: Mol Endocrinol. 2005 Feb;19(2):540-54
references.pmid: 15498831
references.citation: Biochem Pharmacol. 2005 Mar 1;69(5):819-30
references.pmid: 15710359
references.citation: Mol Endocrinol. 2005 Mar;19(3):588-94
references.pmid: 15528269
references.citation: Pharmacol Biochem Behav. 2005 Dec;82(4):712-20
references.pmid: 16388839
references.citation: Pharmacol Ther. 2006 Jun;110(3):503-24
references.pmid: 16337685
references.citation: Trends Pharmacol Sci. 2006 Aug;27(8):402-9
references.pmid: 16822554
references.citation: Biol Psychiatry. 2006 Oct 1;60(7):704-13
references.pmid: 16934764
references.citation: J Biol Chem. 2006 Dec 15;281(50):38879-93
references.pmid: 17050526
references.citation: J Steroid Biochem Mol Biol. 2007 Apr;104(1-2):61-7
references.pmid: 17197174
references.citation: J Biol Chem. 2011 Mar 18;286(11):9875-87
references.pmid: 21209087
references.citation: Curr Top Med Chem. 2011;11(7):860-86
references.pmid: 21291396
references.citation: J Neuroendocrinol. 2012 Jan;24(1):71-81
references.pmid: 21951109
references.citation: J Cereb Blood Flow Metab. 2012 Jan;32(1):1-5
references.pmid: 22008728
references.citation: Curr Mol Med. 2012 May;12(4):398-412
references.pmid: 22348610
references.citation: Biochim Biophys Acta. 2012 Jun;1818(6):1466-76
references.pmid: 22020053
references.citation: Biochim Biophys Acta. 2012 Jun;1818(6):1477-85
references.pmid: 22051019
references.citation: J Biol Chem. 2012 May 4;287(19):15380-94
references.pmid: 22427666
references.citation: Trends Pharmacol Sci. 2012 Nov;33(11):611-20
references.pmid: 22981367
references.citation: Mol Endocrinol. 2012 Nov;26(11):1868-82
references.pmid: 22973050
references.citation: Steroids. 2012 Nov;77(13):1327-34
references.pmid: 22986075
references.citation: Mol Cell Endocrinol. 2013 May 22;371(1-2):34-46
references.pmid: 23246788
references.citation: Recent Pat Endocr Metab Immune Drug Discov. 2013 May;7(2):86-101
references.pmid: 23368281
references.citation: Endocrinology. 2013 Jun;154(6):2156-65
references.pmid: 23525219
references.citation: Pharmacol Rev. 1999 Dec;51(4):629-50
references.pmid: 10581326
references.citation: Endocrinology. 2001 Jan;142(1):502-5
references.pmid: 11145616
references.citation: J Clin Endocrinol Metab. 2001 Feb;86(2):724-31
references.pmid: 11158037
references.citation: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1267-72
references.pmid: 11158628
references.citation: J Neurocytol. 2000 May-Jun;29(5-6):307-26
references.pmid: 11424948
references.citation: Mol Endocrinol. 2001 Dec;15(12):2211-28
references.pmid: 11731621
references.citation: J Clin Endocrinol Metab. 2002 Feb;87(2):589-98
references.pmid: 11836290
references.citation: Science. 2002 May 10;296(5570):1029-31
references.pmid: 12004104
references.citation: J Med Chem. 2002 Sep 12;45(19):4276-81
references.pmid: 12213069
references.citation: J Pharmacol Exp Ther. 2002 Nov;303(2):627-32
references.pmid: 12388644
references.citation: Biochem Pharmacol. 2003 Mar 1;65(5):717-29
references.pmid: 12628485
references.citation: Biochem Pharmacol. 2004 May 15;67(10):1927-32
references.pmid: 15130769
references.citation: J Pharm Pharmacol. 1969 Nov;21(11):784-6
references.pmid: 4390842
references.citation: Proc Natl Acad Sci U S A. 1977 Sep;74(9):3805-9
references.pmid: 20632
references.citation: Endocrinology. 1985 Feb;116(2):567-73
references.pmid: 2981667
references.citation: Eur J Pharmacol. 1985 Mar 26;110(1):41-6
references.pmid: 2988981
references.citation: J Biol Chem. 1986 Jan 15;261(2):576-83
references.pmid: 3001071
references.citation: Endocr Rev. 1986 May;7(2):204-20
references.pmid: 3013606
references.citation: Proc Natl Acad Sci U S A. 1989 Jul;86(13):4897-901
references.pmid: 2544879
references.citation: J Biol Chem. 1989 Dec 5;264(34):20415-21
references.pmid: 2555358
references.citation: J Biol Chem. 1990 Mar 5;265(7):3772-9
references.pmid: 2154488
references.citation: J Biol Chem. 1990 Sep 5;265(25):15015-22
references.pmid: 2168398
references.citation: Pharmacol Biochem Behav. 1990 Aug;36(4):963-71
references.pmid: 2217527
references.citation: Nat Cell Biol. 2007 May;9(5):550-5
references.pmid: 17417626
references.citation: J Biol Chem. 2008 Apr 4;283(14):8837-45
references.pmid: 18250166
references.citation: J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62
references.pmid: 18413427
references.citation: J Med Chem. 2008 Sep 25;51(18):5798-806
references.pmid: 18729350
references.citation: J Bioenerg Biomembr. 2008 Jun;40(3):207-12
references.pmid: 18622693
references.citation: Science. 2009 Jul 24;325(5939):490-3
references.pmid: 19541954
references.citation: Exp Neurol. 2009 Sep;219(1):53-7
references.pmid: 19409385
references.citation: Trends Neurosci. 2010 Jul;33(7):299-306
references.pmid: 20409596
references.citation: Mol Cell Endocrinol. 2010 Oct 7;327(1-2):1-12
references.pmid: 20600583
references.citation: Nat Rev Drug Discov. 2010 Dec;9(12):971-88
references.pmid: 21119734
references.citation: J Biol Chem. 2011 Feb 4;286(5):3460-72
references.pmid: 21106527
references.citation: Pharmacol Rev. 2011 Mar;63(1):243-67
references.pmid: 21245208
references.citation: Neurosci Biobehav Rev. 2013 Jan;37(1):109-22
references.pmid: 23085210
references.citation: J Neuroimmune Pharmacol. 2013 Mar;8(1):51-7
references.pmid: 22956240
references.citation: Mol Pharmacol. 1994 Dec;46(6):1160-7
references.pmid: 7808437
references.citation: Ann N Y Acad Sci. 1994 Nov 30;746:134-42; discussion 142-4, 178-9
references.pmid: 7825871
references.citation: J Biol Chem. 1991 Feb 25;266(6):3682-7
references.pmid: 1847384
references.citation: Eur J Biochem. 1991 Jan 30;195(2):305-11
references.pmid: 1847678
references.citation: J Biol Chem. 1991 Jul 25;266(21):14082-7
references.pmid: 1649835
references.citation: Life Sci. 1991;49(5):325-44
references.pmid: 1649940
references.citation: FASEB J. 1992 Mar;6(6):2311-22
references.pmid: 1347506
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3170-4
references.pmid: 1373486
references.citation: Endocrinology. 2009 Dec;150(12):5438-45
references.pmid: 19846611
references.citation: Structure. 2010 Jun 9;18(6):677-87
references.pmid: 20541505
references.citation: Lipids. 2010 Jul;45(7):567-80
references.pmid: 20559753
references.citation: Biochemistry. 2003 Apr 22;42(15):4506-19
references.pmid: 12693947
references.citation: Fundam Clin Pharmacol. 2003 Aug;17(4):405-17
references.pmid: 12914542
references.citation: Steroids. 2003 Sep;68(7-8):569-85
references.pmid: 12957662
references.citation: Int J Biochem Cell Biol. 2013 Jul;45(7):1212-6
references.pmid: 23518318
references.citation: Neuron. 2013 Jun 19;78(6):1063-74
references.pmid: 23727119
references.citation: JAMA Psychiatry. 2013 Jul;70(7):659-60
references.pmid: 23699915
references.citation: Endocrinology. 2014 Jan;155(1):89-97
references.pmid: 24174323
references.citation: J Nucl Med. 2014 Mar;55(3):466-72
references.pmid: 24516258
references.citation: Science. 2014 Mar 21;343(6177):1363-6
references.pmid: 24653034
references.citation: Mol Ther. 2014 Oct;22(10):1779-91
references.pmid: 24947306
references.citation: J Biol Chem. 2014 Oct 3;289(40):27444-54
references.pmid: 24936060
references.citation: Nat Commun. 2014;5:5452
references.pmid: 25406832
references.citation: Endocrinology. 2015 Jan;156(1):334-45
references.pmid: 25375035
references.citation: Adv Ther. 2015 Jan;32(1):57-68
references.pmid: 25620535
references.citation: Science. 2015 Jan 30;347(6221):551-5
references.pmid: 25635100
references.citation: Science. 2015 Jan 30;347(6221):555-8
references.pmid: 25635101
references.citation: Endocrinology. 2015 Mar;156(3):1033-9
references.pmid: 25535830
references.citation: Biochemistry. 2015 Feb 24;54(7):1441-3
references.pmid: 25635829
references.citation: Curr Pharm Des. 2007;13(23):2385-405
references.pmid: 17692008
references.citation: Eur J Pharmacol. 1991 Dec 12;208(4):307-12
references.pmid: 1667758
references.citation: Endocrinology. 1992 Jun;130(6):3200-6
references.pmid: 1597138
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10598-602
references.pmid: 1279686
references.citation: Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5728-31
references.pmid: 8390677
references.citation: J Pharmacol Exp Ther. 1993 Oct;267(1):462-71
references.pmid: 8229777
references.citation: Mol Pharmacol. 1994 Feb;45(2):201-11
references.pmid: 8114671
references.citation: J Steroid Biochem Mol Biol. 1994 Jun;49(4-6):385-9
references.pmid: 8043504
references.citation: Endocrinology. 1994 Oct;135(4):1576-83
references.pmid: 7925120
references.citation: Science. 1996 Aug 9;273(5276):749-50
references.pmid: 8701325
references.citation: Endocrinology. 1996 Dec;137(12):5707-18
references.pmid: 8940403
references.citation: Steroids. 1997 Jan;62(1):21-8
references.pmid: 9029710
references.citation: Nature. 1997 Jun 19;387(6635):803-5
references.pmid: 9194559
references.citation: Nat Genet. 1997 Jul;16(3):226-34
references.pmid: 9207786
references.citation: Recent Prog Horm Res. 1997;52:1-32
references.pmid: 9238846
references.citation: J Biol Chem. 1997 Oct 31;272(44):28102-6
references.pmid: 9346965
references.citation: Endocrinology. 1997 Dec;138(12):5415-26
references.pmid: 9389527
references.citation: J Biol Chem. 1997 Dec 19;272(51):32129-35
references.pmid: 9405411
references.citation: J Biol Chem. 1998 Jan 23;273(4):2146-52
references.pmid: 9442055
references.citation: J Biol Chem. 1998 Mar 6;273(10):5478-83
references.pmid: 9488670
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3239-44
references.pmid: 9501247