Transduction Is a Major Factor Influencing Receptor Characterization

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Abstract
Two state (agonist-antagonist) receptor systems may explain many discrepancies in receptor classification, but the role of transduction (G protein coupling) may be critical. We propose that in some instances synthetic agonists and antagonists may interact with the receptor in such a way as to modify coupling compared with endogenous agonists, and that the transduction system together with the local environment, may contribute more to the rank order of potency of agonists and antagonists than the receptor subtype as defined by structure. Allosteric interactions at ion channels and receptors require a modification of concepts of coupling. Imidazoline ligands have different efficacy in coupling alpha 2-adrenoceptors to G proteins, compared with adrenaline and noradrenaline, and do not show a marked sodium shift, implying that the sodium site, and by implication the arginine switch, is implicated in the differential coupling. The alpha 2-adrenoceptor labeled with a natural agonist does not show subtype selectivity whereas antagonist-labeled alpha 2-adrenoceptors show subtype selectivity. In the 5-HT1A receptor, palmitoylation (of receptor or G proteins) allows the expression of different agonist states. Thus transduction and G protein coupling must be taken into account in receptor classification, even if the primary classification may be structural.