TY - JOUR T1 - Compromising sigma-1 receptors at the ER renders cytotoxicity to physiologically relevant concentrations of dopamine in a NF-κB/Bcl-2-dependent mechanism: Potential relevance to Parkinson's disease JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.111.190868 SP - jpet.111.190868 AU - Tomohisa Mori AU - Teruo Hayashi AU - Tsung-Ping Su Y1 - 2012/01/01 UR - http://jpet.aspetjournals.org/content/early/2012/03/07/jpet.111.190868.abstract N2 - The endoplasmic reticulum (ER) chaperone sigma-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 the 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 if a relation might exist between Sig-1Rs and DA-induced cytotoxicity in a cellular model by using 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 for 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 NF-κB p105 to the active form of p50 which is known to downregulate the transcription of Bcl-2. Importantly, 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 which would otherwise cause apoptosis. Thus, Sig-1Rs and associated ligands may represent new therapeutic targets for the treatment of Parkinsonism. ER -