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 Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine.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.T he endoplasmic reticulum (ER) plays important roles in cellular functions, including synthesis of proteins and regulation of Ca 2+ signaling between the ER and plasma membrane (1) and between the ER and mitochondria (2-4). However, because the ER interacts with other organelles in the cell, other functions related to the ER remain to be uncovered.The sigma-1 receptor (Sig-1R) (5-8) is an ER chaperone molecule that resides at the ER-mitochondrion interface referred to as the mitochondria-associated ER membrane (MAM), where the Sig-1R ensures proper ER-mitochondrion Ca 2+ signaling for cellular survival (3, 9), as well as sustains the activity of an ER stress sensor IRE1 at the MAM (10). The Sig-1R can translocate from the MAM to plasma membrane of the cell to regulate ion channels and receptors on the plasma membrane (8,(11)(12)(13)(14). Cocaine is a Sig-1R agonist (3) that causes the dissociation of Sig-1R from its cognate binding partner BiP (3,8), and consequently the translocation of Sig-1Rs to the plasma membrane, where Sig-1Rs interact with voltage-gated potassium channel subfamily A member 2 (Kv1.2) to shape the neuronal and behavioral responses to cocaine (15).Cocaine also causes the translocation of Sig-1Rs from the ER to the nucleus (16), where Sig-1Rs are shown to be present at the nuclear envelope (NE) (17). H...

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

“…As HDAC3 has been shown to bind the nuclear envelope protein emerin in muscle progenitors (Demmerle et al, 2013) and HDAC1‐3 have been shown to bind emerin and BAF in neuroblastoma cells (Tsai et al, 2015), we cannot rule out the possibility that tissue‐specific interactions of nuclear envelope proteins with diverse epigenetic enzymes might occur (Batrakou, Las Heras, Czapiewski, Mouras, & Schirmer, 2015; Worman & Schirmer, 2015). Along this line, mutations causing EDMD2 do not impair lamin A/C‐HDAC2 interaction (this study), while defects in emerin‐HDAC3 binding have been reported in EDMD1 (Collins, Ellis, & Holaska, 2017).…”

“…Furthermore, HDAC2 has been shown to suppress p21 expression in human hepatocellular carcinoma via its binding to an Sp1‐binding site (Noh et al, 2011). On the other hand, it has been demonstrated that lamin A/C establishes direct interactions with histone deacetylases including SIRT1 (Cenni et al, 2014; Liu et al, 2012), SIRT6 (Ghosh, Liu, Wang, Hao, & Zhou, 2015), and HDAC1 (Kubben et al, 2016), while lamin partners at the nuclear envelope such as emerin, BAF, and LAP2beta interact with HDAC3 (Demmerle, Koch, & Holaska, 2013) or HDAC2 (Tsai et al, 2015). Moreover, lamin A/C has been demonstrated to bind gene promoters or neighboring domains and this binding has been linked to distinct transcriptional outcomes (Lee, Welton, Smith, & Kennedy, 2009; Lund & Collas, 2013; Mattout et al, 2011).…”

A Review of the Human Sigma-1 Receptor Structure

“…Thus, the S1R membrane topology makes it difficult to rationalize how the receptor could interact with proteins both in the cytoplasm and in the ER lumen. Interactions with several proteins or regions of protein that are found exclusively in the cytoplasm or the nucleus, including the C-terminus of the GluR1 subunit of the ionotropic glutamate receptor [57], STIM1 [58], and emerin [12], are consistent with S1R being a Type I membrane protein with a cytosolic C-terminus. However, an interaction at the C-terminus of S1R with BiP has been shown in cell extracts [2] and in vitro [25].…”

The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems

“…The Sig-1R is also found to translocate to the envelope of the nucleus [14, 15], where the Sig-1R interacts with a nuclear envelope-resident protein emerin and recruits therein a series of chromatin-remodeling factors to regulate the gene transcription [15]. Recently, many studies via experimental or bioinformatics means have identified or proposed the interaction of the Sig-1R with many other functional proteins in the plasma membrane, ER, mitochondria, and even the cytosol.…”