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Mechanisms underlying agonist efficacy

Strange, P.G. (2007) Mechanisms underlying agonist efficacy. Biochemical Society Transactions, 35 (4). pp. 733-736. ISSN 0300-5127

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Agonist efficacy is a measure of how well an agonist can stimulate a response system linked to a receptor. Efficacy can be assessed in functional assays and various parameters (E-max, K-A/EC50, E-max center dot K-A/EC50) determined. The E-max center dot K-A/EC50 parameter provides a good estimate of efficacy across the full range of efficacy. A convenient assay for the efficacy of agonists for some receptors is provided by the [S-35]GTP[S] (guanosine 5'-[gamma-[S-35]thio]triphosphate)-binding assay. in this assay, the normal GTP-binding event in GPCR (G-protein-coupled receptor) activation is replaced by the binding of the non-hydrolysable analogue [S-35]GTP[S]. This assay may be used to profile ligands for their efficacy, and an example here is the D-2 dopamine receptor where an efficacy scale has been set up using this assay. The mechanisms underlying the assay have been probed. The time course of [S-35]GTP[S] binding follows a pseudo-first-order reaction with [S-35]GTP[S] binding reaching equilibrium after approx. 3 h. The [S-35]GTP[S]-binding event is the rate-deter mining step in the assay. Agonists regulate the maximal level of [S-35]GTP[S] bound, rather than the rate constant for binding. The [S-35]GTP[S]-binding assay therefore determines agonist efficacy on the basis of the amount of [S-35]GTP[S] bound rather than the rate of binding.

Item Type:Article
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy
ID Code:13633
Uncontrolled Keywords:agonist efficacy, D-2 dopamine receptor, G-protein-coupled receptor, (GPCR), G-protein cycle, guanosine, 5'-[gamma-[S-35]thioltriphosphate-binding assay ([S-35] GTP[S]-binding, assay), kinetics, D-2 DOPAMINE-RECEPTORS, LIGAND-BINDING, PHARMACOLOGICAL, CHARACTERIZATION, FUNCTIONAL ASSAYS, COUPLED RECEPTOR, CHO CELLS, G-PROTEIN, ACTIVATION, MEMBRANES, MODEL

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