title: The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor.
abstract: Studies of endogenous cannabinoid agonists, such as 2-arachidonylglycerol (2-AG), have revealed their potential to exert modulatory actions on other receptor systems in addition to their ability to activate cannabinoid receptors. This study investigated the effect of cannabinoid ligands on the human adenosine A(3) (hA(3)R) receptor. The endocannabinoid 2-AG was able to inhibit agonist ([125I]N(6)-(4-amino-3-iodobenzyl) adenosine-5'-(N-methyluronamide)--[125I] AB MECA) binding at the hA(3)R. This inhibition occurred over a narrow range of ligand concentration and was characterized by high Hill coefficients suggesting a non-competitive interaction. Furthermore, in the presence of 2-AG, the rate of [125I] AB MECA dissociation was increased, consistent with an action as a negative allosteric modulator of the hA(3)R. Moreover, by measuring intracellular cAMP levels, we demonstrate that 2-AG decreases both the potency of an agonist at the hA(3)R and the basal signalling of this receptor. Since the hA(3)R has been shown to be expressed in astrocytes and microglia, these findings may be particularly relevant in certain pathological states such as cerebral ischemia where levels of 2-AG and anandamide are raised.
authors: Division of Medicinal Chemistry, Leiden/Amsterdam Centre for Drug Research, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. jrlane@chem.leidenuniv.nl
authors: J Robert
authors: JR
authors: Lane
authors: Margot W
authors: MW
authors: Beukers
authors: Thea
authors: T
authors: Mulder-Krieger
authors: Ad P
authors: AP
authors: Ijzerman
mesh_terms: D058918:Adenosine A3 Receptor Antagonists; D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology / Q000502:physiology*; D016466:CHO Cells; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D043684:Receptor, Adenosine A3 / Q000502:physiology*
chemical_list: D058918:Adenosine A3 Receptor Antagonists; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D043684:Receptor, Adenosine A3; C094503:glyceryl 2-arachidonate