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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 47; pp. E6562 - E6570
• Main Authors: Tsai, Shang-Yi A., Chuang, Jian-Ying, Tsai, Meng-Shan, Wang, Xiao-fei, Xi, Zheng-Xiong, Hung, Jan-Jong, Chang, Wen-Chang, Bonci, Antonello, Su, Tsung-Ping
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 24.11.2015; National Academy of Sciences
• Series: PNAS Plus
• Subjects: Animals; Behavior, Animal - drug effects; Biological Sciences; Chromatin; Chromatin Assembly and Disassembly - drug effects; Chromatin Assembly and Disassembly - genetics; Cocaine; Cocaine - pharmacology; DNA-Binding Proteins - metabolism; Drug abuse; Gene expression; Gene Knockdown Techniques; Histone Deacetylase 1 - metabolism; Histone Deacetylase 2 - metabolism; Lamin Type A - metabolism; Membrane Proteins - metabolism; Mice; Molecules; Monoamine Oxidase - genetics; Nuclear Envelope - drug effects; Nuclear Envelope - metabolism; Nuclear Proteins - metabolism; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; PNAS Plus; Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Protein Transport - drug effects; Proteins; Rats; Receptors, sigma - metabolism; Rodents; Sigma-1 Receptor; Sp3 Transcription Factor; Substance Withdrawal Syndrome; Transcription, Genetic - drug effects; deprenyl; sigma-1 receptor; emerin; MAOB; cocaine
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1518894112

The endoplasmic reticulum (ER), although functioning as protein synthesis machinery in the cell, plays other important roles that have yet to be fully unveiled. We found here that the ER can directly send an envoy protein, the sigma-1 receptor (Sig-1R), to the nuclear envelope (NE), where the Sig-1R begins to recruit chromatin-remodeling molecules through the NE integral protein emerin to control gene transcription. Thus, the Sig-1R represents a molecule that shapes the functional connection between the NE and the DNA. We also demonstrate in this study that cocaine, a Sig-1R agonist, down-regulates the critical enzyme monoamine oxidase B that influences the cocaine-induced dopamine level in a dopamine transporter-independent manner via this never-before-described, to our knowledge, Sig-1R-linked genomic action of cocaine. 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.