Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 109, Issue 51, Pages 21134-21139Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1202906109
Keywords
allosteric modulation; psychopharmacology; GPCR; inflammation; neuroprotection
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Funding
- German research foundation Deutsche Forschungsgemeinschaft [FOR926]
- Institut National de la Sante et de la Recherche Medicale
- Aquitaine Region
- European Research Council [ERC-2010-StG-260515]
- Fondation pour la Recherche Medicale
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- PRONEX
- Fundacao de Amparo a Pesquisa e Inovacao do Estado de Santa Catarina (FAPESC)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico-CNPq
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq)
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Allosteric modulation of G-protein-coupled receptors represents a key goal of current pharmacology. In particular, endogenous allosteric modulators might represent important targets of interventions aimed at maximizing therapeutic efficacy and reducing side effects of drugs. Here we show that the anti-inflammatory lipid lipoxin A(4) is an endogenous allosteric enhancer of the CB1 cannabinoid receptor. Lipoxin A(4) was detected in brain tissues, did not compete for the orthosteric binding site of the CB1 receptor (vs. H-3-SR141716A), and did not alter endocannabinoid metabolism (as opposed to URB597 and MAFP), but it enhanced affinity of anandamide at the CB1 receptor, thereby potentiating the effects of this endocannabinoid both in vitro and in vivo. In addition, lipoxin A(4) displayed a CB1 receptor-dependent protective effect against beta-amyloid (1-40)-induced spatial memory impairment in mice. The discovery of lipoxins as a class of endogenous allosteric modulators of CB1 receptors may foster the therapeutic exploitation of the endocannabinoid system, in particular for the treatment of neurodegenerative disorders.
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