The endocannabinoid 2-arachidonylglycerol is a negative allosteric modulator of the human A3 adenosine receptor

Biochem Pharmacol. 2010 Jan 1;79(1):48-56. doi: 10.1016/j.bcp.2009.07.024. Epub 2009 Aug 7.


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.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine A3 Receptor Antagonists*
  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • Arachidonic Acids / pharmacology
  • Arachidonic Acids / physiology*
  • CHO Cells
  • Cannabinoid Receptor Modulators / antagonists & inhibitors*
  • Cannabinoid Receptor Modulators / pharmacology
  • Cannabinoid Receptor Modulators / physiology*
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Down-Regulation / drug effects*
  • Down-Regulation / physiology
  • Endocannabinoids*
  • Glycerides / pharmacology
  • Glycerides / physiology*
  • Humans
  • Protein Binding / drug effects
  • Protein Binding / physiology
  • Receptor, Adenosine A3 / physiology*


  • Adenosine A3 Receptor Antagonists
  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Glycerides
  • Receptor, Adenosine A3
  • glyceryl 2-arachidonate