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Mechanisms of G protein activation via the D-2 dopamine receptor: evidence for persistent receptor/G protein interaction after agonist stimulation

Quirk, K., Roberts, D.J. and Strange, P.G. (2007) Mechanisms of G protein activation via the D-2 dopamine receptor: evidence for persistent receptor/G protein interaction after agonist stimulation. British Journal of Pharmacology, 151 (1). pp. 125-133. ISSN 0007-1188

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To link to this article DOI: 10.1038/sj.bjp.0707197

Abstract/Summary

Background and purpose: The aim of this report is to study mechanisms of G protein activation by agonists. Experimental approach: The association and dissociation of guanosine 5'-O-(3-[S-35] thio) triphosphate ([S-35] GTP gamma S) binding at G proteins in membranes of CHO cells stably transfected with the human dopamine D-2short receptor was studied in the presence of a range of agonists. Key results: Binding of [S-35] GTPgS was dissociable in the absence of agonist and dissociation was accelerated both in rate and extent by dopamine, an effect which was blocked by the dopamine D-2 receptor antagonist raclopride and by suramin, which inhibits receptor/G protein interaction. A range of agonists of varying efficacy increased the rate of dissociation of [S-35] GTPgS binding, with the more efficacious agonists resulting in faster dissociation. Agonists were able to dissociate about 70% of the pre-bound [S-35] GTPgS, leaving a component which may not be accessible to the agonist-bound receptor. The dissociable component of the [S-35] GTPgS binding was reduced with longer association times and increased [S-35] GTPgS concentrations. Conclusions and implications: These data are consistent with [S-35] GTPgS binding being initially to receptor-linked G proteins and then to G proteins which have separated from the agonist bound receptor. Under the conditions used typically for [S-35] GTPgS binding assays, therefore, much of the agonist-receptor complex remains in proximity to G proteins after they have been activated by agonist.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy
ID Code:13653
Uncontrolled Keywords:D-2 dopamine receptor, G proteins, [S-35]GTP gamma S association, [S-35]GTP gamma S dissociation, suramin, agonist mechanisms, GUANINE-NUCLEOTIDES, LIGAND-BINDING, MEMBRANES, EFFICACY, CELLS, DISSOCIATION, GUANOSINE, AFFINITY, ASSAYS

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