Growth hormone secretagogues and growth hormone releasing peptides act as orthosteric super-agonists but not allosteric regulators for activation of the G protein G{alpha}o1 by the ghrelin receptor (original) (raw)

Bennett, K.A., Langmead, C.J., Wise, A. and Milligan, G.(2009) Growth hormone secretagogues and growth hormone releasing peptides act as orthosteric super-agonists but not allosteric regulators for activation of the G protein G{alpha}o1 by the ghrelin receptor.Molecular Pharmacology, 76(4), pp. 802-811. (doi: 10.1124/mol.109.056101)

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Publisher's URL: http://dx.doi.org/10.1124/mol.109.056101

Abstract

A series of growth hormone secretagogues act as agonists at the ghrelin receptor and have been described as 'ago-allosteric' ligands due to an ability to also modulate the maximum efficacy and potency of ghrelin (Holst et al., 2005). In membranes prepared from cells co-expressing the human ghrelin receptor and the G protein G{alpha}o1 each of MK-677, GHRP-6 and L-692585 functioned as direct agonists, and each displayed higher efficacy than ghrelin. The effect of multiple, fixed concentrations of each of these ligands on the function and concentration-dependence of ghrelin and the effect of multiple, fixed concentrations of ghrelin on the action of MK-677, GHRP-6 and L-692585 was analyzed globally according to a modified version of an operational model of allosterism which accounts for allosteric modulation of affinity, efficacy and allosteric agonism. Each of the data sets was best fitted by a model of simple competition between a partial and a full agonist. Both positive and negative allosteric modulators are anticipated to alter the kinetics of binding of an orthosteric agonist. However, none of the proposed ago-allosteric regulators tested had any effect on the dissociation kinetics of [His[125I]]-ghrelin and GHRP-6 and MK-677 were able to fully displace [His[125I]]-ghrelin from the receptor. At least in the system tested, each of the ligands acted in a simple competitive fashion with ghrelin as demonstrated by analysis according to a model whereby ghrelin is a partial agonist with respect to each of the synthetic agonists tested

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