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J. Biol. Chem., Vol. 278, Issue 30, 28089-28100, July 25, 2003

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Chronic Stimulation of D1 Dopamine Receptors in Human SK-N-MC Neuroblastoma Cells Induces Nitric-oxide Synthase Activation and Cytotoxicity^*

Jun Chen, Christophe Wersinger and Anita Sidhu 

From the Department of Pediatrics, Georgetown University, Washington, D. C. 20007

Elevated synaptic levels of dopamine may induce striatal neurodegeneration in L-DOPA-unresponsive parkinsonism subtype of multiple system atrophy (MSA-P subtype), multiple system atrophy, and methamphetamine addiction. We examined the participation of dopamine and D1 dopamine receptors in the genesis of postsynaptic neurodegeneration. Chronic treatment of human SK-N-MC neuroblastoma cells with dopamine or H₂O₂ increased NO production and accelerated cytotoxicity, as indexed by enhanced nitrite levels and cell death. The antioxidant sodium metabisulfite or SCH 23390, a D1 dopamine receptor-selective antagonist, partially blocked dopamine effects but together ablated dopamine-mediated cytotoxicity, indicating the participation of both autoxidation and D1 receptor stimulation. Direct activation of D1 dopamine receptors with SKF R-38393 caused cytotoxicity, which was refractory to sodium metabisulfite. Dopamine and SKF R-38393 induced overexpression of the nitric-oxide synthase (NOS) isoforms neuronal NOS, inducible NOS (iNOS), and endothelial NOS in a protein kinase A-dependent manner. Functional studies showed that 60% of total NOS activity was due to activation of iNOS. The NOS inhibitor N(G)-nitro-L-arginine methyl ester and genistein, wortmannin, or NF-B SN50, inhibitors of protein tyrosine kinases phosphatidylinositol 3-kinase and NF-B, respectively, reduced nitrite production by dopamine and SKF R-38393 but were less effective in attenuating H₂O₂-mediated effects. In rat striatal neurons, dopamine and SKF R-38393, but not H₂O₂, accelerated cell death through increased expression of neuronal NOS and iNOS but not endothelial NOS. These data demonstrate a novel pathway of dopamine-mediated postsynaptic oxidative stress and cell death through direct activation of NOS enzymes by D1 dopamine receptors and its associated signaling pathways.

Received for publication, March 26, 2003 , and in revised form, May 5, 2003.

^* This study was supported in part by National Institutes of Health Grants NS-34914 and NS-41555 and a National Alliance for Research on Schizophrenia and Depression Investigator Award. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Laboratory of Molecular Neurochemistry, The Research Bldg., Rm. W222, 3970 Reservoir Rd., NW, Washington, D. C. 20007. Tel.: 202-687-0282; Fax: 202-687-0279; E-mail: sidhua{at}georgetown.edu.

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