Metabolism, bioactions and physiological significance of 2-arachidonoylglycerol, a novel lipid mediator

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1. Development of novel analogs of 2-arachidonoylglycerol (2-AG). In this study, first, we have developed several metabolically stable analogs of 2-AG. These analogs would be useful tools in the elucidation of the possible biological activities of 2-AG.2. The generation of 2-AG in the brain and its physiological meanings. Next, we examined the synthesis of 2-AG in rat brain synaptosomes. We found that the level of 2-AG was augmented markedly in depolarized synaptosomes. We found that 30 % of newly formed 2-AG was released from depolarized synaptosomes, indicating that 2-AG can act as an intercellular mediator. Next, we examined the effect of SR141716A on the release of glutamate from depolarized synaptosomes. We found that treatment of synaptosomes with SR141716A significantly enhanced the release of glutamate from synaptosomes upon depolarization. These results strongly suggest that 2-AG released from stimulated neurons may have an important physiological role in the attenuation of ne … More urotransmission through acting on the CB1 receptor expressed mainly in the presynapse.3. Physiological meanings of 2-AG in the immune system. We found that 2-AG induces rapid phosphorylation and activation of the p42/44 MAP kinase in HL-60 cells. In addition to the p42/44 MAP kinase, we found that rapid phosphorylation of the p38MAP kinase and c-Jun N-terminal kinase takes place in 2-AG-stimulated HL-60 cells. We also found that 2-AG induces the migration of HL-60 cells differentiated into macrophage-like cells. The 2-AG-induced migration of HL-60 cells was markedly reduced when the cells were pretreated with either SR144528 or PTX, suggesting that the migration was mediated through the CB2 receptor and Gi/Go. We also found that the addition of 2-AG to HL-60 cells enhanced the production of chemokines such as IL-8 and MCP- 1 through a CB2 receptor- and Gi/Go-dependent mechanism. Based on the experimental results concerning cell migration and chemokine production, we propose that 2-AG has a positive rather than negative role during inflammatory reactions and immune responses. Less