The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements

Chuang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

115

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 Treatment of cocaine-withdrawn rats with the MAOB inhibitor deprenyl completely alleviated the behavioral sensitization to cocaine.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

Section: Discussionsupporting

confidence: 57%

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

Chuang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2015

115

“…Activation of s receptors has been shown to decrease oxidative injury and nitrosative stress in various models. It was recently shown, using s-receptor knockout mice, that s-1 has a dual function of both reducing oxidative stress and activating antioxidant response elements (Pal et al, 2012). In microglia, stimulation of s receptors by DTG reduces NO production in response to lipopolysaccharide (Hall et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Sigma Receptors with Afobazole Blocks Activation of Microglia and Reduces Toxicity Caused by Amyloid-β_25–35

Behensky

Yasny

Shuster

et al. 2013

J Pharmacol Exp Ther

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the leading cause of senile dementia in the United States. Accumulation of amyloid-b (Ab) and the effects of this peptide on microglial cells contribute greatly to the etiology of AD. Experiments were carried out to determine whether the panselective s-receptor agonist afobazole can modulate microglial response to the cytotoxic Ab fragment, Ab [25][26][27][28][29][30][31][32][33][34][35] . Treatment with afobazole decreased microglial activation in response to Ab, as indicated by reduced membrane ruffling and cell migration. The effects of afobazole on Ab 25-35 -evoked migration were concentration dependent and consistent with s-receptor activation. When afobazole was coapplied with either BD-1047 [N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide] or rimcazole, which are s-1-and s-2-selective antagonists, respectively, the inhibition of Ab 25-35 -induced migration by afobazole was reduced. Prolonged exposure of microglia to Ab 25-35 resulted in glial cell death that was associated with increased expression of the proapoptotic protein Bax and the death protease caspase-3. Coapplication of afobazole with Ab 25-35 decreased the number of cells expressing both Bax and caspase-3 and resulted in a concomitant enhancement in cell survival. Although afobazole inhibited activation of microglia cells by Ab [25][26][27][28][29][30][31][32][33][34][35] , it preserved normal functional responses in these cells after exposure to the amyloid peptide. Intracellular calcium increases induced by ATP were depressed in microglia after 24-hour exposure to Ab [25][26][27][28][29][30][31][32][33][34][35] . However, coincubation in afobazole returned these responses to near control levels. Therefore, stimulation of s-1 and s-2 receptors by afobazole prevents Ab [25][26][27][28][29][30][31][32][33][34][35] activation of microglia and inhibits Ab 25-35 -associated cytotoxicity, suggesting that afobazole may be useful for AD therapeutics.

“…A specific functional role has not been ascribed to this cysteine. Because the S1R has been associated with various in vivo mechanisms to suppress cellular oxidative stress (Bucolo et al, 2006;Tuerxun et al, 2010;Pal et al, 2012), perhaps cysteine 94 participates in redox reactions to maintain an intracellular reducing environment. An alanine residue when substituted for cysteine 94 does not significantly affect the binding of the S1R agonist [ The 50 amino acid loop joining the two TM sequences has been examined by NMR and found to contain three short helical segments, labeled as cH1, cH2, and cH3 (Ortega-Roldan et al, 2015) (Fig.…”

Section: Structural Features Of the S1rmentioning

confidence: 99%

Biochemical Pharmacology of the Sigma-1 Receptor

2015

Self Cite

The sigma-1 receptor (S1R) is a 223 amino acid two transmembrane (TM) pass protein. It is a non-ATP-binding nonglycosylated ligand-regulated molecular chaperone of unknown three-dimensional structure. The S1R is resident to eukaryotic mitochondrial-associated endoplasmic reticulum and plasma membranes with broad functions that regulate cellular calcium homeostasis and reduce oxidative stress. Several multitasking functions of the S1R are underwritten by chaperone-mediated direct (and indirect) interactions with ion channels, G-protein coupled receptors and cell-signaling molecules involved in the regulation of cell growth. The S1R is a promising drug target for the treatment of several neurodegenerative diseases related to cellular stress. In vitro and in vivo functional and molecular characteristics of the S1R and its interactions with endogenous and synthetic small molecules have been discovered by the use of pharmacologic, biochemical, biophysical, and molecular biology approaches. The S1R exists in monomer, dimer, tetramer, hexamer/octamer, and higher oligomeric forms that may be important determinants in defining the pharmacology and mechanism(s) of action of the S1R. A canonical GXXXG in putative TM2 is important for S1R oligomerization. The ligand-binding regions of S1R have been identified and include portions of TM2 and the TM proximal regions of the C terminus. Some client protein chaperone functions and interactions with the cochaperone 78-kDa glucose-regulated protein (binding immunoglobulin protein) involve the C terminus. Based on its biochemical features and mechanisms of chaperone action the possibility that the S1R is a member of the small heat shock protein family is discussed.