Physiological roles of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand

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We found that 2-arachidonoylglycerol (2-AG) induces rapid transient increases in intracellular free Ca^<2+> concentrations in HL-60 cells which express the cannabinoid CB2 receptor. We then examined the structure-activity relationship of 2-AG and other cannabinoid receptor ligands in detail. We found that an ether-linked analogue of 2-AG possesses significant biological activity, indicating that the structure of 2-AG itself, but not its metabolite, is actually recognized by the CB2 receptor molecule. Noticeably, the activities of ether-linked analogues and amide bond-containing analogues of 2-AG were considerably lower than that of 2-AG, suggesting that the presence of an ester linkage is crucially important for exhibiting strong agonistic activity. In contrast to 2-AG, anandamide was found to act as a weak partial agonist toward the CB2 receptor. The activity of Δ^9-tetrahydrocannabinol, at major constituent of marijuana, was also low. We further examined the activities of various 2-A … More G analogues and classical and synthetic cannabinoids. The activities of monoacylglycerols containing various saturated, monoenoic and dienoic fatty acids were very low. 2-AG acted as one of the most potent agonists toward the CB2 receptor. We concluded the CB2 receptor is originally a 2-AG receptor, and that Δ^9-tetrahydrocannabinol may interfere with the actions of 2-AG thereby eliciting various pharmacological effects. We then examined the level of 2-AG in the brain. Rat brain was found to contain 0.23 nmol/g tissue of 2-AG.We found that the level of 2-AG was elevated markedly in picrotoxinin-administered rat brain and in post-decapitative ischemic rat brain. We also found that a large amount of 2-AG was generated when brain homogenate was incubated in the presence of Ca^<2+>. We confirmed that 2-AG can be generated from inositol phospholipids through the action of phospholipase C and subsequent diacylglycerol lipase activity ; it seems very likely that the function of the cannabinoid receptors are closely related to increased inositol phospholipid metabolism. 2-AG rapidly generated in the brain after stimulation mat play important physiological roles in the regulation of neurotransmission. Less