NDLI: Protean agonism at histamine H3 receptors in vitro and in vivo

Content Provider	PubMed Central
Author	Florence, Gbahou Rouleau, Agnès Morisset, Séverine Parmentier, Régis Crochet, Sylvain Lin, Jian-sheng Xavier, Ligneau Tardivel-lacombe, Joël Stark, Holger Walter, Schunack Robin, Ganellin C. Schwartz, Jean-charles Arrang, Jean-michel
Copyright Year	2003
Abstract	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 H3-receptor ligand, acts as a protean agonist at recombinant H3 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 H3 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.
Related Links	http://dx.doi.org/10.1073/pnas.1932276100
Ending Page	11091
Page Count	6
Starting Page	11086
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	19
Volume Number	100
Language	English
Publisher	National Academy of Sciences
Publisher Date	2003-09-16
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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Protean agonism at histamine H3 receptors in vitro and in vivo.

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Protean agonism at histamine H3 receptors in vitro and in vivo

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Protean agonism at histamine H3 receptors in vitro and in vivo.

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Protean agonism at histamine H3 receptors in vitro and in vivo