title: The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements.
abstract: Sigma-1 receptors are associated with Alzheimer's disease, major depressive disorders, and schizophrenia. These receptors show progrowth/antiapoptotic properties via their chaperoning functions to counteract ER (endoplasmic reticulum) stress, to block neurodegeneration, and to regulate neuritogenesis. The sigma-1 receptor knock out mouse offered an opportunity to assess possible mechanisms by which the sigma-1 receptor modulates cellular oxidative stress. Nuclear magnetic resonance (NMR) metabolomic screening of the WT (wild type) and sigma-1 KO (knockout) livers was performed to investigate major changes in metabolites that are linked to oxidative stress. Significant changes in protein levels were also identified by two-dimensional (2D) gel electrophoresis and mass spectrometry. Increased levels of the antioxidant protein peroxiredoxin 6 (Prdx6), and the ER chaperone BiP (GRP78) compared to WT littermates were detected. Oxidative stress was measured in WT and sigma-1 KO mouse liver homogenates, in primary hepatocytes and in lung homogenates. Furthermore, sigma-1 receptor mediated activation of the antioxidant response element (ARE) to upregulate NAD(P)H quinone oxidoreductase 1 (NQO1) and superoxide dismutase 1 (SOD1) mRNA expression in COS cells was shown by RT PCR. These novel functions of the sigma-1 receptor were sensitive to well-known sigma ligands via their antagonist/agonist properties.
authors.affiliation: Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
authors.forename: Arindam
authors.initials: A
authors.lastname: Pal
authors.forename: Dominique
authors.initials: D
authors.lastname: Fontanilla
authors.forename: Anupama
authors.initials: A
authors.lastname: Gopalakrishnan
authors.forename: Young-Kee
authors.initials: YK
authors.lastname: Chae
authors.forename: John L
authors.initials: JL
authors.lastname: Markley
authors.forename: Arnold E
authors.initials: AE
authors.lastname: Ruoho
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D000091342:Endoplasmic Reticulum Chaperone BiP; D055786:Gene Knockout Techniques; D006168:Guinea Pigs; D051379:Mice; D018384:Oxidative Stress / Q000235:genetics; D040901:Proteomics; D017480:Receptors, sigma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics*; D000097605:Sigma-1 Receptor
chemical_list: D000975:Antioxidants; D000091342:Endoplasmic Reticulum Chaperone BiP; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C000717248:Hspa5 protein, mouse