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Requirement of G and c-Src in D2 Dopamine Receptor-Mediated Nuclear Factor-B Activation

Department of Pharmacology, College of Medicine, University of Illinois, Chicago, Illinois

The D2 dopamine receptor (D2R) was examined for its ability to mediate nuclear factor-B (NF-B) activation through G proteins. Stimulation of D2R-transfected HeLa cells with its agonist quinpirole induced the expression of a NF-B luciferase reporter and formation of NF-B-DNA complex. This response was blocked by pertussis toxin, and by the G scavengers transducin and -adrenergic receptor kinase 1 carboxyl-terminal fragment. Unlike G_i-coupled chemoattractant receptors, D2R activated NF-B without an increase in phospholipase C- activity, and the response was only slightly affected by the phosphoinositide 3-kinase inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). In contrast, treatment with genistein and 4-amino-1-tert-butyl-3-(p-methylphenyl)pyrazolo[3,4-d] pyrimidine abolished the induced NF-B activation, suggesting involvement of protein tyrosine kinases. Activation of D2R led to phosphorylation of c-Src at Tyr-418, and expression of a kinase-deficient c-Src inhibited D2R-mediated NF-B activation. The D2R-mediated NF-B activation was not dependent on epidermal growth factor (EGF) receptor transactivation since 4-(3'-chloroanilino)-6,7-dimethoxyquinazoline (AG1478), an EGF receptor-selective tyrphostin used at 1 µM, blocked EGF-induced NF-B activation but not the quinpirole-induced response. In addition, the D2R-mediated NF-B activation was enhanced by over-expression of -arrestin 1. These results suggest that D2R-mediated NF-B activation requires G and c-Src, and possibly involves -arrestin 1.

Address correspondence to: Richard D. Ye, Department of Pharmacology, M/C 868, University of Illinois at Chicago, 835 S. Wolcott Avenue, Chicago, IL 60612. E-mail: yer{at}uic.edu

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