Protean agonism at histamine H3 receptors in vitro and in vivo

G protein-coupled receptors (GPCRs) are allosteric proteins that adopt inactive (R) and active (R * ) conformations in equilibrium. R * is promoted by agonists or occurs spontaneously, leading to constitutive activity of the receptor. Conversely, inverse agonists promote R and decrease constitutive...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2003-09, Vol.100 (19), p.11086-11091
Main Authors: Gbahou, Florence, Rouleau, Agnès, Morisset, Séverine, Parmentier, Régis, Crochet, Sylvain, Lin, Jian-Sheng, Ligneau, Xavier, Tardivel-Lacombe, Joël, Stark, Holger, Schunack, Walter, Ganellin, C Robin, Schwartz, Jean-Charles, Arrang, Jean-Michel
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
CHO Cells
Cricetinae
Histamine
Histamine Antagonists - pharmacology
Imidazoles - pharmacology
In Vitro Techniques
Life Sciences
Mitogen-Activated Protein Kinases - metabolism
Pharmacology
Proteins
Receptors, Histamine H3 - drug effects
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Summary:G protein-coupled receptors (GPCRs) are allosteric proteins that adopt inactive (R) and active (R * ) conformations in equilibrium. R * is promoted by agonists or occurs spontaneously, leading to constitutive activity of the receptor. Conversely, inverse agonists promote R and decrease constitutive activity. The existence of another pharmacological entity, referred to as “protean” agonists (after Proteus, the Greek god who could change shape), was assumed on theoretical grounds. It was predicted from the existence of constitutive activity that a same ligand of this class could act either as an agonist or an inverse agonist at the same GPCR. Here, we show that proxyfan, a high-affinity histamine H 3 -receptor ligand, acts as a protean agonist at recombinant H 3 receptors expressed in the same Chinese hamster ovary cells. In support of the physiological relevance of the process, we show that proxyfan also behaves as a protean agonist at native H 3 receptors known to display constitutive activity. On neurochemical and behavioral responses in rodents and cats, proxyfan displays a spectrum of activity ranging from full agonism to full inverse agonism. Thus, protean agonism demonstrates the existence of ligand-directed active states LR * different from, and competing with, constitutively active states R * of GPCRs, and defines a pharmacological entity with important therapeutic implications.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1932276100