title: Compromising σ-1 receptors at the endoplasmic reticulum render cytotoxicity to physiologically relevant concentrations of dopamine in a nuclear factor-κB/Bcl-2-dependent mechanism: potential relevance to Parkinson's disease.
abstract: The endoplasmic reticulum (ER) chaperone σ-1 receptor (Sig-1R) is cytoprotective against ER stress-induced apoptosis. The level of Sig-1Rs in the brain was reported to be lower in early parkinsonian patients. Because dopamine (DA) toxicity is well known to be involved in the etiology of Parkinson's disease, we tested in this study whether a relationship might exist between Sig-1Rs and DA-induced cytotoxicity in a cellular model by using Chinese hamster ovary (CHO) cells. DA in physiological concentrations (e.g., lower than 10 μM) does not cause apoptosis. However, the same concentrations of DA cause apoptosis in Sig-1R knockdown CHO cells. In search of a mechanistic explanation, we found that unfolded protein response is not involved. Rather, the level of protective protein Bcl-2 is critically involved in this DA/Sig-1R knockdown-induced apoptosis. Specifically, the DA/Sig-1R knockdown causes a synergistic proteasomal conversion of nuclear factor κB (NF-κB) p105 to the active form of p50, which is known to down-regulate the transcription of Bcl-2. It is noteworthy that the DA/Sig-1R knockdown-induced apoptosis is blocked by the overexpression of Bcl-2. Our results therefore indicate that DA is involved in the activation of NF-κB and suggest that endogenous Sig-1Rs are tonically inhibiting the proteasomal conversion/activation of NF-κB caused by physiologically relevant concentrations of DA that would otherwise cause apoptosis. Thus, Sig-1Rs and associated ligands may represent new therapeutic targets for the treatment of parkinsonism.
authors.affiliation: Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Teruo
authors.initials: T
authors.lastname: Hayashi
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004298:Dopamine / Q000494:pharmacology*; D015259:Dopamine Agents / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D020868:Gene Silencing; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D017480:Receptors, sigma / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D000097605:Sigma-1 Receptor
chemical_list: D004298:Dopamine; D015259:Dopamine Agents; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D013481:Superoxides; D000097605:Sigma-1 Receptor