title: Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope.
abstract: The sigma-1 receptor (Sig-1R) chaperone at the endoplasmic reticulum (ER) plays important roles in cellular regulation. Here we found a new function of Sig-1R, in that it translocates from the ER to the nuclear envelope (NE) to recruit chromatin-remodeling molecules and regulate the gene transcription thereof. Sig-1Rs mainly reside at the ER-mitochondrion interface. However, on stimulation by agonists such as cocaine, Sig-1Rs translocate from ER to the NE, where Sig-1Rs bind NE protein emerin and recruit chromatin-remodeling molecules, including lamin A/C, barrier-to-autointegration factor (BAF), and histone deacetylase (HDAC), to form a complex with the gene repressor specific protein 3 (Sp3). Knockdown of Sig-1Rs attenuates the complex formation. Cocaine was found to suppress the gene expression of monoamine oxidase B (MAOB) in the brain of wild-type but not Sig-1R knockout mouse. A single dose of cocaine (20 mg/kg) in rats suppresses the level of MAOB at nuclear accumbens without affecting the level of dopamine transporter. Daily injections of cocaine in rats caused behavioral sensitization. Withdrawal from cocaine in cocaine-sensitized rats induced an apparent time-dependent rebound of the MAOB protein level to about 200% over control on day 14 after withdrawal. Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine. Our results demonstrate a role of Sig-1R in transcriptional regulation and suggest cocaine may work through this newly discovered genomic action to achieve its addictive action. Results also suggest the MAOB inhibitor deprenyl as a therapeutic agent to block certain actions of cocaine during withdrawal.
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224;
authors.forename: Shang-Yi A
authors.initials: SY
authors.lastname: Tsai
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224; The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, Taipei 11031, Taiwan;
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Chuang
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224;
authors.forename: Meng-Shan
authors.initials: MS
authors.lastname: Tsai
authors.affiliation: Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224;
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Molecular Targets and Medication Discovery Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224;
authors.forename: Zheng-Xiong
authors.identifier: http://orcid.org/0000-0001-6482-8104
authors.initials: ZX
authors.lastname: Xi
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Tainan 70101, Taiwan;
authors.forename: Jan-Jong
authors.initials: JJ
authors.lastname: Hung
authors.affiliation: Graduate Institute of Medical Science, Taipei Medical University, Taipei 11031, Taiwan;
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Cellular Neurobiology Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224; Department of Neurology, University of California, San Francisco, CA 94608; Solomon H. Snyder Neuroscience Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Antonello
authors.initials: A
authors.lastname: Bonci
authors.affiliation: Cellular Pathobiology Section, Integrative Neuroscience Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224; TSU@intra.nida.nih.gov.
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects* / Q000235:genetics; D003042:Cocaine / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism; D034904:Lamin Type A / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008995:Monoamine Oxidase / Q000235:genetics; D009685:Nuclear Envelope / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D051705:Sp3 Transcription Factor; D013375:Substance Withdrawal Syndrome; D014158:Transcription, Genetic / Q000187:drug effects*; D000097605:Sigma-1 Receptor
chemical_list: D003042:Cocaine; D004268:DNA-Binding Proteins; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D034904:Lamin Type A; D008565:Membrane Proteins; D008995:Monoamine Oxidase; D009687:Nuclear Proteins; D017480:Receptors, sigma; D051705:Sp3 Transcription Factor; D000097605:Sigma-1 Receptor; C501960:Banf1 protein, mouse; C092710:emerin
keywords: MAOB; cocaine; deprenyl; emerin; sigma-1 receptor