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Journal of Biochemistry Advance Access originally published online on March 4, 2007
Journal of Biochemistry 2007 141(5):687-697; doi:10.1093/jb/mvm070
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© 2007 The Japanese Biochemical Society.

Depolarization-induced Rapid Generation of 2-Arachidonoylglycerol, an Endogenous Cannabinoid Receptor Ligand, in Rat Brain Synaptosomes

Saori Oka1, Shunsuke Arai1, Keizo Waku1, Akira Tokumura2 and Takayuki Sugiura1,*

1Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa 199-0195 Japan; and 2Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima, Tokushima 770-8505, Japan

*To whom correspondence should be addressed. Tel: 81-426-85-3746, Fax: 81-426-85-1345, E-mail: sugiurat{at}pharm.teikyo-u.ac.jp

Received November 27, 2006; Accepted February 24, 2007


  Abstract

2-Arachidonoylglycerol (2-AG) is an endogenous ligand for the cannabinoid receptors with a variety of potent biological activities. In this study, we first examined the effects of potassium-induced depolarization on the level of 2-AG in rat brain synaptosomes. We found that a significant amount of 2-AG was generated in the synaptosomes following depolarization. Notably, depolarization did not affect the levels of other molecular species of monoacylglycerols. Furthermore, the level of anandamide was very low and did not change markedly following depolarization. It thus appeared that the depolarization-induced accelerated generation is a unique feature of 2-AG. We obtained evidence that phospholipase C is involved in the generation of 2-AG in depolarized synaptosomes: U73122 [GenBank] , a phospholipase C inhibitor, markedly reduced the depolarization-induced generation of 2-AG, and the level of diacylglycerol was rapidly elevated following depolarization. A significant amount of 2-AG was released from synaptosomes upon depolarization. Interestingly, treatment of the synaptosomes with SR141716A, a CB1 receptor antagonist, augmented the release of glutamate from depolarized synaptosomes. These results strongly suggest that the endogenous ligand for the cannabinoid receptors, i.e. 2-AG, generated through increased phospholipid metabolism upon depolarization, plays an important role in attenuating glutamate release from the synaptic terminals by acting on the CB1 receptor.

Key Words: anandamide, 2-arachidonoylglycerol, cannabinoid, monoacylglycerol, synaptosomes

Abbreviations: 2-AG, 2-arachidonoylglycerol; DFP, diisopropylfluorophosphate; DSE, depolarization-induced suppression of excitation; DSI, depolarization-induced suppression of inhibition; LTD, long-term depression; {Delta}9-THC, {Delta}9-tetrahydrocannabinol


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