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We examined the effect of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, on the intracellular free Ca 2؉ concentrations in HL-60 cells that express the cannabinoid CB2 receptor. We found that 2-arachidonoylglycerol induces a rapid transient increase in intracellular free Ca 2؉ concentrations in HL-60 cells. The response was affected by neither cyclooxygenase inhibitors nor lipoxygenase inhibitors, suggesting that arachidonic acid metabolites are not involved. Consistent with this notion, free arachidonic acid was devoid of any agonistic activity. Importantly, the Ca 2؉ transient induced by 2-arachidonoylglycerol was blocked by pretreatment of the cells with SR144528, a CB2 receptor-specific antagonist, but not with SR141716A, a CB1 receptor-specific antagonist, indicating the involvement of the CB2 receptor but not the CB1 receptor in this cellular response. G i or G o is also assumed to be involved, because pertussis toxin treatment of the cells abolished the response. We further examined the structure-activity relationship. We found that 2-arachidonoylglycerol is the most potent compound among a number of naturally occurring cannabimimetic molecules. Interestingly, anandamide and N-palmitoylethanolamine, other putative endogenous ligands, were found to be a weak partial agonist and an inactive ligand, respectively. These results strongly suggest that the CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic natural ligand for the CB2 receptor that is abundant in the immune system. ⌬ 9 -Tetrahydrocannabinol (⌬ 9 -THC), 1 a major psychoactive constituent of marijuana, is known to exert a variety of pharmacological effects on laboratory animals and humans. When administered orally or intravenously, ⌬ 9 -THC induces reduced spontaneous motor activity, analgesia, heightened sensory awareness, euphoria, and impairment of short-term memory (1). ⌬ 9 -THC is also known to exert profound effects on several biological systems other than the central nervous system; for example, ⌬ 9 -THC exhibits potent immunosuppressive activities (2-12). The mechanism underlying such diverse actions of ⌬ 9 -THC remained obscure until the late 1980s. -THC itself bind to a specific receptor site(s) thereby eliciting a variety of responses. To date, two types of cannabinoid receptors have been identified as follows: the CB1 receptor expressed primarily in the nervous system (14), and the CB2 receptor expressed mainly in the immune system (15). Both are seven transmembrane, G protein-coupled receptors, and they share 44% overall identity (68% identity for transmembrane domains) (15).The discovery of specific receptors for cannabinoids prompted the search for endogenous ligands. To date, two types of arachidonic acid-containing molecules, anandamide (16) and 2-arachidonoylglycerol (2-AG) (17, 18), have been reported as putative endogenous cannabinoid receptor ligands. Anandamide was isolated from porcine brain (16), and 2-AG was isolated from rat brain (17) and canine gut...

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Over 100 different phospholipid molecular species are known to be present in mammalian cells and tissues. Fatty acid remodeling systems for phospholipids including acyl-CoA: lysophospholipid acyltransferases, CoA-dependent and CoA-independent transacylation systems and lysophospholipase/transacylase are involved in the biosynthesis of these molecular species. Acyl-CoA:1-acyl-2-lysophospholipid acyltransferase prefers polyunsaturated fatty acyl-CoAs as acyl donors while acyl-CoA:2-acyl-1-lysophospholipid acyltransferase prefers saturated fatty acyl-CoAs. Therefore, the acyl-CoA:lysophospholipid acyltransferase system is involved in the synthesis of the phospholipid molecular species containing sn-1 saturated and sn-2 unsaturated fatty acids. The CoA-dependent transacylation system catalyzes the transfer of fatty acids esterified in phospholipids to lysophospholipids in the presence of CoA without the generation of free fatty acids. The CoA-dependent transacylation reaction in rat liver exhibits strict fatty acid specificity, i.e., three types of fatty acids (20:4, 18:2, and 18:0) are transferred. On the other hand, the CoA-independent transacylase catalyzes the transfer of C20 and C22 polyunsaturated fatty acids from diacyl phospholipids to various lysophospholipids, in particular, ether-containing lysophospholipids, in the absence of any cofactors. The CoA-independent transacylase is assumed to be involved in the accumulation of polyunsaturated fatty acids in ether-containing phospholipids and in the removal of deleterious ether-containing lysophospholipids. These acyltransferases and transacylases are involved in not only the remodeling of fatty acids but also the synthesis and degradation of some bioactive lipids and their precursors. In this review, the properties of these fatty acid remodeling systems and their possible roles in the biosynthesis of bioactive lipids are described.