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0026-895X/97/061060-10$3.00/0
Copyright © by The American Society for Pharmacology and Experimental Therapeutics
All rights of reproduction in any form reserved.
MOLECULAR PHARMACOLOGY 51:1060-1069 (1997).

Somatostatin5 Receptor-Mediated [35S]Guanosine-5'-O-(3-thio)triphosphate Binding: Agonist Potencies and the Influence of Sodium Chloride on Intrinsic Activity

Andrea J. Williams, Anton D. Michel, Wasyl Feniuk, and Patrick P. A. Humphrey

Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Cambridge, CB2 1QJ, UK

We studied the activation of the human somatostatin5 receptor recombinantly expressed in CHO-K1 cells by using some newly available agonists and antagonists. Somatostatin-28 bound to this receptor with a higher affinity than somatostatin-14 and was more potent in increasing [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgamma S) binding. Somatostatin-14-induced [35S]GTPgamma S binding to membranes from this cell line was decreased in a concentration-related manner by increasing concentrations of GDP and sodium chloride. At 50 mM (low) sodium, agonist EC50 values for stimulating [35S]GTPgamma S binding were lower than those at 150 mM (high) sodium and were closer to their respective affinity estimates (dissociation equilibrium constants) for binding to the receptor in the absence of sodium. Both agonist binding to the high affinity state of the receptor and agonist-induced [35S]GTPgamma S binding were abolished by pertussis toxin pretreatment. The putative somatostatin5 receptor-selective ligand L-362,855, unlike somatostatin-14 and somatostatin-28, showed differential intrinsic activity for stimulation of [35S]GTPgamma S binding, behaving as a partial agonist in high sodium and a full agonist in low sodium. In contrast, BIM-23056 did not behave as an agonist under any conditions studied but was able to antagonize somatostatin-14-induced [35S]GTPgamma S binding. We conclude that measurement of [35S]GTPgamma S binding mediated by somatostatin receptor activation in the presence of different concentrations of sodium chloride provides a useful functional assay for assessing the relative agonist efficacies of novel ligands identified from radioligand binding studies.

Copyright © by The American Society for Pharmacology and Experimental Therapeutics


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