title: S-Glutathionylation and Redox Protein Signaling in Drug Addiction.
abstract: Drug addiction is a chronic relapsing disorder that comes at a high cost to individuals and society. Therefore understanding the mechanisms by which drugs exert their effects is of prime importance. Drugs of abuse increase the production of reactive oxygen and nitrogen species resulting in oxidative stress. This change in redox homeostasis increases the conjugation of glutathione to protein cysteine residues; a process called S-glutathionylation. Although traditionally regarded as a protective mechanism against irreversible protein oxidation, accumulated evidence suggests a more nuanced role for S-glutathionylation, namely as a mediator in redox-sensitive protein signaling. The reversible modification of protein thiols leading to alteration in function under different physiologic/pathologic conditions provides a mechanism whereby change in redox status can be translated into a functional response. As such, S-glutathionylation represents an understudied means of post-translational protein modification that may be important in the mechanisms underlying drug addiction. This review will discuss the evidence for S-glutathionylation as a redox-sensing mechanism and how this may be involved in the response to drug-induced oxidative stress. The function of S-glutathionylated proteins involved in neurotransmission, dendritic spine structure, and drug-induced behavioral outputs will be reviewed with specific reference to alcohol, cocaine, and heroin.
authors.affiliation: Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA.
authors.forename: Jacqueline S
authors.initials: JS
authors.lastname: Womersley
authors.affiliation: Department of Cellular and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address: uys@musc.edu.
authors.forename: Joachim D
authors.initials: JD
authors.lastname: Uys
mesh_terms: D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D015398:Signal Transduction; D019966:Substance-Related Disorders / Q000378:metabolism*
chemical_list: D005978:Glutathione
keywords: S-glutathionylation; addiction; alcohol; cocaine; heroin; posttranslational modification; redox; redox signaling
references.citation: Biochem Pharmacol. 2002 Sep;64(5-6):1057-64
references.pmid: 12213605
references.citation: Alcohol Clin Exp Res. 2003 Feb;27(2):232-43
references.pmid: 12605072
references.citation: Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):964-72
references.pmid: 15998251
references.citation: Toxicol Lett. 2013 Jun 7;219(3):298-306
references.pmid: 23542814
references.citation: Nature. 2001 Mar 15;410(6826):376-80
references.pmid: 11268215
references.citation: Front Behav Neurosci. 2014 Mar 07;8:70
references.pmid: 24639635
references.citation: Brain Res. 2006 May 17;1089(1):44-54
references.pmid: 16638611
references.citation: Ann N Y Acad Sci. 2003 Dec;1010:667-70
references.pmid: 15033808
references.citation: Neuropharmacology. 2004;47 Suppl 1:242-55
references.pmid: 15464141
references.citation: Eur J Pharmacol. 2014 Apr 5;728:183-7
references.pmid: 24291102
references.citation: Biochim Biophys Acta. 2013 May;1830(5):3165-72
references.pmid: 23416063
references.citation: Prog Neurobiol. 2000 Dec;62(6):649-71
references.pmid: 10880854
references.citation: Neuropharmacology. 2006 Dec;51(7-8):1137-45
references.pmid: 16938317
references.citation: Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):1956-61
references.pmid: 8700866
references.citation: Environ Toxicol Pharmacol. 2006 Jan;21(1):80-5
references.pmid: 21783642
references.citation: Ann N Y Acad Sci. 2004 Oct;1025:345-50
references.pmid: 15542735
references.citation: Neurochem Res. 2006 Mar;31(3):303-11
references.pmid: 16733807
references.citation: Neurosci Lett. 2000 Nov 3;293(3):171-4
references.pmid: 11036188
references.citation: Neurotox Res. 2013 Jan;23(1):92-102
references.pmid: 22791409
references.citation: Brain Res. 2007 Oct 31;1178:28-37
references.pmid: 17888892
references.citation: Brain Res Brain Res Rev. 2001 Dec;38(1-2):1-19
references.pmid: 11750924
references.citation: Mol Cell Neurosci. 2014 Jul;61:56-64
references.pmid: 24938665
references.citation: Neurosci Lett. 1998 Oct 9;255(1):49-52
references.pmid: 9839724
references.citation: Parkinsonism Relat Disord. 2002 Sep;8(6):395-400
references.pmid: 12217626
references.citation: Biochemistry. 2001 Nov 27;40(47):14134-42
references.pmid: 11714266
references.citation: Alcohol Clin Exp Res. 1997 Jun;21(4):596-601
references.pmid: 9194910
references.citation: Free Radic Res. 2005 May;39(5):471-80
references.pmid: 16036322
references.citation: Addict Biol. 2016 May;21(3):560-74
references.pmid: 25787124
references.citation: Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2191-6
references.pmid: 14769920
references.citation: J Biol Chem. 2005 Jan 28;280(4):2750-8
references.pmid: 15533936
references.citation: Food Chem Toxicol. 2001 Feb;39(2):109-17
references.pmid: 11267703
references.citation: Chang Gung Med J. 2009 Mar-Apr;32(2):148-54
references.pmid: 19403004
references.citation: Brain Res. 2001 Nov 30;920(1-2):125-33
references.pmid: 11716818
references.citation: Glia. 2011 Oct;59(10):1387-401
references.pmid: 21590811
references.citation: Nat Med. 2001 Apr;7(4):416-7
references.pmid: 11283665
references.citation: Biochim Biophys Acta. 2013 May;1830(5):3139-42
references.pmid: 23127894
references.citation: Biochem J. 2000 Jul 15;349(Pt 2):567-78
references.pmid: 10880356
references.citation: J Neurochem. 2009 Jul;110(1):363-77
references.pmid: 19457111
references.citation: J Neurosci. 2004 Jan 28;24(4):865-76
references.pmid: 14749431
references.citation: Arch Physiol Biochem. 2014 Oct;120(4):123-30
references.pmid: 25112365
references.citation: Pharmacogenet Genomics. 2005 Dec;15(12):891-3
references.pmid: 16272961
references.citation: Eur J Biochem. 2000 Aug;267(16):4912-6
references.pmid: 10931173
references.citation: Brain Res. 2002 Jul 19;944(1-2):90-6
references.pmid: 12106669
references.citation: Curr Opin Pharmacol. 2007 Aug;7(4):381-91
references.pmid: 17662654
references.citation: Brain Res. 2000 Mar 6;858(1):1-8
references.pmid: 10700589
references.citation: PLoS One. 2014;9(4):e94787
references.pmid: 24740405
references.citation: Am J Drug Alcohol Abuse. 2010 Jul;36(4):228-32
references.pmid: 20560843
references.citation: Int J Mol Sci. 2013;14(10):21021-44
references.pmid: 24145751
references.citation: Neuropharmacology. 2015 May;92:80-9
references.pmid: 25596492
references.citation: Neurosci Lett. 2002 Aug 9;328(2):93-6
references.pmid: 12133563
references.citation: J Plant Physiol. 2008 Sep 8;165(13):1390-403
references.pmid: 18171593
references.citation: Biochem Pharmacol. 1997 Feb 21;53(4):539-45
references.pmid: 9105405
references.citation: Neuroscientist. 2011 Jun;17(3):321-36
references.pmid: 21498812
references.citation: Neuroscience. 2014 Mar 14;262:107-17
references.pmid: 24406441
references.citation: Antioxid Redox Signal. 2005 Mar-Apr;7(3-4):348-66
references.pmid: 15706083
references.citation: Alcohol Clin Exp Res. 2001 May;25(5):717-25
references.pmid: 11371721
references.citation: J Mol Cell Cardiol. 2012 Mar;52(3):559-67
references.pmid: 21784079
references.citation: Fundam Clin Pharmacol. 2008 Aug;22(4):439-45
references.pmid: 18705754
references.citation: Proc Natl Acad Sci U S A. 2002 Mar 19;99(6):3505-10
references.pmid: 11904414
references.citation: Arch Biochem Biophys. 2002 Oct 15;406(2):229-40
references.pmid: 12361711
references.citation: J Neurosci. 1998 Mar 1;18(5):1848-59
references.pmid: 9465009
references.citation: Curr Opin Pharmacol. 2007 Aug;7(4):398-403
references.pmid: 17611156
references.citation: Neuroscience. 2011 Nov 24;196:1-15
references.pmid: 21925237
references.citation: J Neurochem. 1998 Nov;71(5):2071-8
references.pmid: 9798932
references.citation: Biochem Pharmacol. 2007 May 1;73(9):1257-69
references.pmid: 17098212
references.citation: Brain Res Dev Brain Res. 2003 Nov 12;145(2):249-62
references.pmid: 14604765
references.citation: Neurosci Bull. 2014 Dec;30(6):1025-35
references.pmid: 25304015
references.citation: Biomed Res Int. 2013;2013:484613
references.pmid: 24455696
references.citation: Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):999-1010
references.pmid: 15998254
references.citation: Eur J Pharmacol. 2011 Jan 10;650(1):157-62
references.pmid: 20969850
references.citation: Am J Med Genet. 1997 Jul 25;74(4):439-42
references.pmid: 9259381
references.citation: Adv Exp Med Biol. 2012;970:81-95
references.pmid: 22351052
references.citation: Toxicology. 2010 Sep 30;276(1):11-7
references.pmid: 20600547
references.citation: Eur J Biochem. 2000 Aug;267(16):4928-44
references.pmid: 10931175
references.citation: Front Biosci. 1999 Jun 15;4:D541-50
references.pmid: 10369807
references.citation: Biochem J. 2004 Aug 1;381(Pt 3):e1-2
references.pmid: 15270699
references.citation: Neuropharmacology. 2005 Jun;48(7):965-74
references.pmid: 15857623
references.citation: Biochim Biophys Acta. 2013 May;1830(5):3143-53
references.pmid: 22995213
references.citation: J Neurochem. 2009 Jul;110(2):486-95
references.pmid: 19457110
references.citation: Brain Res Rev. 2011 Jun 24;67(1-2):209-25
references.pmid: 21315761
references.citation: J Biol Chem. 2004 May 28;279(22):23710-8
references.pmid: 15031283
references.citation: Acta Histochem. 2014 Jan;116(1):182-90
references.pmid: 23953641
references.citation: Biochem Biophys Res Commun. 2014 Oct 24;453(3):345-9
references.pmid: 25264102
references.citation: Crit Rev Biochem Mol Biol. 2013 Mar-Apr;48(2):173-81
references.pmid: 23356510
references.citation: Neuropsychopharmacology. 2010 Jan;35(1):217-38
references.pmid: 19710631
references.citation: Adicciones. 2014;26(4):360-70
references.pmid: 25578004
references.citation: Annu Rev Pharmacol Toxicol. 2006;46:215-34
references.pmid: 16402904
references.citation: Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8746-51
references.pmid: 15937104
references.citation: Am J Pathol. 2009 Jul;175(1):54-65
references.pmid: 19498008
references.citation: PLoS One. 2015;10(1):e0114285
references.pmid: 25617894
references.citation: Arch Pharm Res. 2011 Dec;34(12):2155-62
references.pmid: 22210043
references.citation: Alcohol. 1997 May-Jun;14(3):213-23
references.pmid: 9160798
references.citation: J Biol Chem. 2002 Dec 13;277(50):48295-302
references.pmid: 12376535
references.citation: Biol Chem. 2003 Apr;384(4):505-16
references.pmid: 12751781
references.citation: CNS Drugs. 2014 Feb;28(2):95-106
references.pmid: 24442756
references.citation: J Neurochem. 2002 Aug;82(3):458-67
references.pmid: 12153471
references.citation: Alcohol Clin Exp Res. 2011 Nov;35(11):2050-62
references.pmid: 21631543
references.citation: J Cell Mol Med. 2004 Apr-Jun;8(2):201-12
references.pmid: 15256068
references.citation: Mol Cell Biochem. 2015 Jun;404(1-2):143-59
references.pmid: 25735949
references.citation: Biol Trace Elem Res. 2011 Jul;142(1):55-66
references.pmid: 20544301
references.citation: J Neurochem. 2011 Sep;118(5):902-14
references.pmid: 21668448
references.citation: Curr Opin Chem Biol. 2011 Feb;15(1):103-12
references.pmid: 21216657
references.citation: Free Radic Biol Med. 2007 Sep 15;43(6):883-98
references.pmid: 17697933
references.citation: Front Pharmacol. 2012 Nov 01;3:189
references.pmid: 23125836
references.citation: Methods Enzymol. 2010;474:289-96
references.pmid: 20609917
references.citation: J Neurochem. 2010 Aug;114(3):675-84
references.pmid: 20477932
references.citation: Addict Biol. 2015 Mar;20(2):285-96
references.pmid: 24506432
references.citation: Free Radic Res. 2005 Jun;39(6):573-80
references.pmid: 16036334
references.citation: J Pharmacol Exp Ther. 2001 Jan;296(1):1-6
references.pmid: 11123355
references.citation: Curr Top Behav Neurosci. 2013;13:3-30
references.pmid: 21744309
references.citation: Front Pharmacol. 2014 Nov 25;5:259
references.pmid: 25505416
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2005 May 5;135B(1):5-9
references.pmid: 15729709
references.citation: Molecules. 2010 Jul;15(7):4984-5011
references.pmid: 20657404
references.citation: Bratisl Lek Listy. 2007;108(9):393-8
references.pmid: 18225476
references.citation: J Biol Chem. 2001 Dec 21;276(51):47763-6
references.pmid: 11684673
references.citation: Am J Physiol Lung Cell Mol Physiol. 2014 Mar 1;306(5):L429-41
references.pmid: 24441868
references.citation: Biochem Pharmacol. 2000 Sep 1;60(5):615-23
references.pmid: 10927019
references.citation: Addiction. 2003 Dec;98 Suppl 2:31-43
references.pmid: 14984240
references.citation: Am J Drug Alcohol Abuse. 2010 Jan;36(1):13-7
references.pmid: 20141391
references.citation: Alcohol. 2015 May;49(3):259-63
references.pmid: 25771148
references.citation: Alcohol Alcohol. 1997 Jan-Feb;32(1):65-9
references.pmid: 9131893
references.citation: Open J Apoptosis. 2012 Jul;1(2):null
references.pmid: 24380057
references.citation: Mol Neurobiol. 2004 Apr;29(2):139-54
references.pmid: 15126682
references.citation: Eur J Biochem. 2000 Aug;267(16):4904-11
references.pmid: 10931172
references.citation: Neuropsychopharmacology. 2011 Nov;36(12):2551-60
references.pmid: 21796101
references.citation: PLoS Comput Biol. 2010 Feb;6(2):e1000670
references.pmid: 20169176
references.citation: Biochim Biophys Acta. 2014 Aug;1844(8):1335-43
references.pmid: 24657586
references.citation: Neurosci Lett. 2003 Oct 9;349(3):201-5
references.pmid: 12951203
references.citation: J Pharmacol Exp Ther. 2011 May;337(2):487-93
references.pmid: 21303920
references.citation: Drug Metab Rev. 2011 May;43(2):179-93
references.pmid: 21351850
references.citation: Free Radic Biol Med. 2011 Jul 15;51(2):299-313
references.pmid: 21558000
references.citation: Biochem J. 2012 Apr 1;443(1):3-11
references.pmid: 22417747
references.citation: Antioxid Redox Signal. 2012 Mar 15;16(6):471-5
references.pmid: 22136616
references.citation: Biochem Pharmacol. 2006 Feb 28;71(5):551-64
references.pmid: 16337153
references.citation: Front Psychiatry. 2011 Nov 29;2:64
references.pmid: 22144966
references.citation: Scand J Clin Lab Invest. 2010 Apr;70(2):71-4
references.pmid: 19929269
references.citation: Basic Clin Pharmacol Toxicol. 2006 Aug;99(2):153-61
references.pmid: 16918717
references.citation: J Biol Chem. 2002 Nov 8;277(45):43505-11
references.pmid: 12189155
references.citation: Antioxid Redox Signal. 2012 Dec 15;17(12):1728-37
references.pmid: 22540427
references.citation: Ann N Y Acad Sci. 1999 Jun 29;877:140-56
references.pmid: 10415648
references.citation: Subst Use Misuse. 2014 Sep;49(11):1385-91
references.pmid: 24708432
references.citation: Eur J Pharm Sci. 2012 Aug 15;46(5):279-92
references.pmid: 22484331
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4147-52
references.pmid: 17360491
references.citation: Ann N Y Acad Sci. 2008 Oct;1141:22-57
references.pmid: 18991950
references.citation: Antioxid Redox Signal. 2007 Feb;9(2):233-44
references.pmid: 17115936
references.citation: Oxid Med Cell Longev. 2015;2015:269371
references.pmid: 25949770
references.citation: Neurochem Int. 2008 Jul;53(1-2):1-11
references.pmid: 18513832
references.citation: Biol Psychiatry. 2008 Feb 1;63(3):338-40
references.pmid: 17719565
references.citation: FASEB J. 2004 Aug;18(11):1246-8
references.pmid: 15180957
references.citation: J Biol Chem. 2013 Sep 13;288(37):26497-504
references.pmid: 23861399
references.citation: Drug Alcohol Depend. 2012 Jul 1;124(1-2):42-9
references.pmid: 22261181
references.citation: Life Sci. 2005 May 27;77(2):183-93
references.pmid: 15862603
references.citation: Psychopharmacology (Berl). 2002 Dec;165(1):51-9
references.pmid: 12474118
references.citation: Front Neuroanat. 2014 Oct 02;8:110
references.pmid: 25324733
references.citation: Front Pharmacol. 2014 Jan 08;4:172
references.pmid: 24409148
references.citation: Neurotox Res. 2008 Oct;14(2-3):169-83
references.pmid: 19073424
references.citation: J Med Chem. 1996 Mar 29;39(7):1494-508
references.pmid: 8691480
references.citation: Biochem Pharmacol. 1999 Nov 15;58(10):1579-85
references.pmid: 10535748
references.citation: Trends Biochem Sci. 2013 Dec;38(12):592-602
references.pmid: 24120033
references.citation: Neuropharmacology. 2004;47 Suppl 1:33-46
references.pmid: 15464124
references.citation: Annu Rev Neurosci. 2006;29:565-98
references.pmid: 16776597
references.citation: Neurosci Lett. 1997 Apr 18;226(1):29-32
references.pmid: 9153634
references.citation: J Biol Chem. 2009 Jan 2;284(1):436-45
references.pmid: 18990698
references.citation: Front Cell Dev Biol. 2014 Nov 17;2:68
references.pmid: 25453035
references.citation: Int J Mol Med. 2013 Aug;32(2):497-502
references.pmid: 23708443
references.citation: Neuroscience. 2000;101(1):67-76
references.pmid: 11068137
references.citation: Br J Pharmacol. 1999 May;127(2):343-8
references.pmid: 10385232
references.citation: J Biol Chem. 2015 Jun 5;290(23):14637-46
references.pmid: 25903132
references.citation: Cerebellum. 2008;7(3):332-47
references.pmid: 18418667
references.citation: Chem Res Toxicol. 2008 Jan;21(1):172-88
references.pmid: 18052107
references.citation: Arch Toxicol. 2005 Mar;79(3):123-8
references.pmid: 15654607
references.citation: Addict Biol. 2015 Sep;20(5):927-40
references.pmid: 25736529
references.citation: Neurosci Lett. 2005 Oct 14;387(1):53-6
references.pmid: 16085363
references.citation: Curr Opin Neurobiol. 2012 Jun;22(3):383-8
references.pmid: 21963169
references.citation: Neuroscience. 2012 Aug 30;218:196-205
references.pmid: 22609933
references.citation: Alcohol Clin Exp Res. 1997 Feb;21(1):82-5
references.pmid: 9046377
references.citation: Toxicology. 2002 Sep 30;179(1-2):9-19
references.pmid: 12204538
references.citation: Front Neurosci. 2015 Jan 22;8:444
references.pmid: 25657617
references.citation: Eur J Neurosci. 2005 Sep;22(5):1214-20
references.pmid: 16176364
references.citation: Arch Biochem Biophys. 2011 Apr 1;508(1):1-12
references.pmid: 21176768
references.citation: Cancer Res. 2006 Jul 1;66(13):6800-6
references.pmid: 16818657
references.citation: Neuroscience. 2008 Aug 26;155(3):649-58
references.pmid: 18619523
references.citation: Biochem Soc Trans. 2005 Dec;33(Pt 6):1378-81
references.pmid: 16246123
references.citation: Antioxid Redox Signal. 2004 Feb;6(1):63-74
references.pmid: 14713336
references.citation: Neuroscience. 2013 Oct 22;251:2-20
references.pmid: 23867772
references.citation: Ann N Y Acad Sci. 2008 Oct;1139:89-102
references.pmid: 18991853
references.citation: Addict Biol. 2015 Jul;20(4):663-75
references.pmid: 24975938