Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope

Shang-Yi A Tsai, Jian-Ying Chuang, Meng-Shan Tsai, Xiao-Fei Wang, Zheng-Xiong Xi, Jan-Jong Hung, Wen-Chang Chang, Antonello Bonci, Tsung-Ping Su

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine.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.

Original languageEnglish
Pages (from-to)E6562-70
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number47
DOIs
Publication statusPublished - Nov 24 2015

    Fingerprint

Keywords

  • Animals
  • Behavior, Animal
  • Chromatin Assembly and Disassembly
  • Cocaine
  • DNA-Binding Proteins
  • Gene Knockdown Techniques
  • Histone Deacetylase 1
  • Histone Deacetylase 2
  • Lamin Type A
  • Membrane Proteins
  • Mice
  • Monoamine Oxidase
  • Nuclear Envelope
  • Nuclear Proteins
  • Nucleus Accumbens
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Transport
  • Rats
  • Receptors, sigma
  • Sp3 Transcription Factor
  • Substance Withdrawal Syndrome
  • Transcription, Genetic
  • Journal Article
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

Cite this