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Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus.
J Pharmacol Exp Ther. 1998 May; 285(2):496-505.JP

Abstract

This study examined the signal transduction correlates of mu opioid agonist efficacy in two systems: mu receptor-transfected mMOR-CHO cell and rat thalamic membranes. The potency and maximal stimulation of [35S]GTP gamma S binding by various agonists was measured in the presence of excess GDP and compared with receptor binding affinity under identical assay conditions. Results showed that the relative maximal stimulation produced by these agonists was greater in mMOR-CHO cell than in rat thalamic membranes; some drugs that were full agonists in mMOR-CHO cells were partial agonists in the thalamus, and some partial agonists in the transfected cells were full antagonists in the thalamus. Furthermore, there was receptor reserve for G-protein activation by some agonists in mMOR-CHO cell membranes, but no receptor reserve was detected in rat thalamic membranes. Saturation analysis of agonist-stimulated [35S]GTP gamma S binding revealed that full agonists produced both a higher Bmax and apparent affinity of [35S]GTP gamma S binding than partial agonists. Correlation of the Bmax and KD of agonist-stimulated [35S]GTP gamma S binding with agonist intrinsic efficacy revealed only a moderate correlation with either parameter alone, but a highly significant correlation (r > 0.9) with a combination of the two parameters (Bmax/KD). These results suggest that the intrinsic efficacy of agonists at G-protein-coupled receptors is determined primarily by the ability of the agonist-occupied receptor to promote high-affinity GTP binding to the G-protein and to catalytically activate a maximal number G-proteins.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

9580589

Citation

Selley, D E., et al. "Signal Transduction Correlates of Mu Opioid Agonist Intrinsic Efficacy: Receptor-stimulated [35S]GTP Gamma S Binding in mMOR-CHO Cells and Rat Thalamus." The Journal of Pharmacology and Experimental Therapeutics, vol. 285, no. 2, 1998, pp. 496-505.
Selley DE, Liu Q, Childers SR. Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus. J Pharmacol Exp Ther. 1998;285(2):496-505.
Selley, D. E., Liu, Q., & Childers, S. R. (1998). Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus. The Journal of Pharmacology and Experimental Therapeutics, 285(2), 496-505.
Selley DE, Liu Q, Childers SR. Signal Transduction Correlates of Mu Opioid Agonist Intrinsic Efficacy: Receptor-stimulated [35S]GTP Gamma S Binding in mMOR-CHO Cells and Rat Thalamus. J Pharmacol Exp Ther. 1998;285(2):496-505. PubMed PMID: 9580589.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Signal transduction correlates of mu opioid agonist intrinsic efficacy: receptor-stimulated [35S]GTP gamma S binding in mMOR-CHO cells and rat thalamus. AU - Selley,D E, AU - Liu,Q, AU - Childers,S R, PY - 1998/5/15/pubmed PY - 1998/5/15/medline PY - 1998/5/15/entrez SP - 496 EP - 505 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 285 IS - 2 N2 - This study examined the signal transduction correlates of mu opioid agonist efficacy in two systems: mu receptor-transfected mMOR-CHO cell and rat thalamic membranes. The potency and maximal stimulation of [35S]GTP gamma S binding by various agonists was measured in the presence of excess GDP and compared with receptor binding affinity under identical assay conditions. Results showed that the relative maximal stimulation produced by these agonists was greater in mMOR-CHO cell than in rat thalamic membranes; some drugs that were full agonists in mMOR-CHO cells were partial agonists in the thalamus, and some partial agonists in the transfected cells were full antagonists in the thalamus. Furthermore, there was receptor reserve for G-protein activation by some agonists in mMOR-CHO cell membranes, but no receptor reserve was detected in rat thalamic membranes. Saturation analysis of agonist-stimulated [35S]GTP gamma S binding revealed that full agonists produced both a higher Bmax and apparent affinity of [35S]GTP gamma S binding than partial agonists. Correlation of the Bmax and KD of agonist-stimulated [35S]GTP gamma S binding with agonist intrinsic efficacy revealed only a moderate correlation with either parameter alone, but a highly significant correlation (r > 0.9) with a combination of the two parameters (Bmax/KD). These results suggest that the intrinsic efficacy of agonists at G-protein-coupled receptors is determined primarily by the ability of the agonist-occupied receptor to promote high-affinity GTP binding to the G-protein and to catalytically activate a maximal number G-proteins. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/9580589/Signal_transduction_correlates_of_mu_opioid_agonist_intrinsic_efficacy:_receptor_stimulated_[35S]GTP_gamma_S_binding_in_mMOR_CHO_cells_and_rat_thalamus_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9580589 DB - PRIME DP - Unbound Medicine ER -