The Life Cycle of the Endocannabinoids: Formation and Inactivation

  • Stephen P. H. AlexanderEmail author
  • David A. Kendall
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 1)


In this chapter, we summarise the current thinking about the nature of endocannabinoids. In describing the life cycle of these agents, we highlight the synthetic and catabolic enzymes suggested to be involved. For each of these, we provide a systematic analysis of information on sequence, subcellular and cellular distribution, as well as physiological and pharmacological substrates, enhancers and inhibitors, together with brief descriptions of the impact of manipulating enzyme levels through genetic mechanisms (dealt with in more detail in the chapter “Genetic Models of the Endocannabinoid System” by Monory and Lutz, this volume). In addition, we describe experiments investigating the stimulation of endocannabinoid synthesis and release in intact cell systems.


2-arachidonoylglycerol Anandamide Diacylglcyerol lipase Endocannabinoid turnover Fatty acid amide hydrolase N-acylphosphatidylethanolamine phospholipase D 







Anandamide, N-arachidonoylethanolamine






Diacylglycerol lipase


Depolarization-evoked suppression of inhibition




Epoxyeicosatrienoic acid


Exchange protein activated by cyclic AMP


Fatty acid amide hydrolase






Lysophospholipase C


Lysophospholipase D






Monoacylglycerol lipase


N-Acylethanolamine acid amidase
















Phospholipase A1


Phospholipase A2


Phospholipase B


Phospholipase C


Phospholipase D






  1. Ahn DK, Choi HS, Yeo SP et al. (2007) Blockade of central cyclooxygenase (COX) pathways enhances the cannabinoid-induced antinociceptive effects on inflammatory temporomandibular joint (TMJ) nociception. Pain 132:23–32PubMedGoogle Scholar
  2. Aneetha H, O'Dell DK, Tan B et al. (2009) Alcohol dehydrogenase-catalyzed in vitro oxidation of anandamide to N-arachidonoyl glycine, a lipid mediator: Synthesis of N-acyl glycinals. Bioorg Med Chem Lett 19:237–241PubMedGoogle Scholar
  3. Aoki J, Inoue A, Makide K et al. (2007) Structure and function of extracellular phospholipase A1 belonging to the pancreatic lipase gene family. Biochimie 89:197–204PubMedGoogle Scholar
  4. Artmann A, Petersen G, Hellgren LI et al. (2008) Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim Biophys Acta-Mol Cell Biol L 1781:200–212Google Scholar
  5. Bajo M, Roberto M, Schweitzer P (2009) Differential alteration of hippocampal excitatory synaptic transmission by cannabinoid ligands. J Neurosci Res 87:766–775PubMedGoogle Scholar
  6. Basanez G, Nieva JL, Goni FM et al. (1996) Origin of the lag period in the phospholipase C cleavage of phospholipids in membranes. Concomitant vesicle aggregation and enzyme activation. Biochemistry 35:15183–15187PubMedGoogle Scholar
  7. Bequet F, Uzabiaga F, Desbazeille M et al. (2007) CB1 receptor-mediated control of the release of endocannabinoids (as assessed by microdialysis coupled with LC/MS) in the rat hypothalamus. Eur J Neurosci 26:3458–3464PubMedGoogle Scholar
  8. Berdyshev EV, Schmid PC, Krebsbach RJ et al. (2001) Activation of PAF receptors results in enhanced synthesis of 2-arachidonoylglycerol (2-AG) in immune cells. FASEB J 15:2171–2178PubMedGoogle Scholar
  9. Bisogno T, Maurelli S, Melck D et al. (1997) Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem 272:3315–3323PubMedGoogle Scholar
  10. Bisogno T, Melck D, De Petrocellis L et al. (1999) Phosphatidic acid as the biosynthetic precursor of the endocannabinoid 2-arachidonoylglycerol in intact mouse neuroblastoma cells stimulated with ionomycin. J Neurochem 72:2113–2119PubMedGoogle Scholar
  11. Bisogno T, Howell F, Williams G et al. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468PubMedGoogle Scholar
  12. Bisogno T, Ortar G, Petrosino S et al. (2009) Development of a potent inhibitor of 2-arachidonoylglycerol hydrolysis with antinociceptive activity in vivo. Biochim Biophys Acta 1791:53–60PubMedGoogle Scholar
  13. Bobrov MY, Shevchenko VP, Yudushkin IA et al. (2000) Hydrolysis of anandamide and eicosapentaenoic acid ethanolamide in mouse splenocytes. Biochemistry (Mosc) 65:615–619Google Scholar
  14. Brindley DN (2004) Lipid phosphate phosphatases and related proteins: Signaling functions in development, cell division, and cancer. J Cell Biochem 92:900–912PubMedGoogle Scholar
  15. Cadas H, Gaillet S, Beltramo M et al. (1996a) Biosynthesis of an endogenous cannabinoid precursor in neurons and its control by calcium and cAMP. J Neurosci 16:3934–3942PubMedGoogle Scholar
  16. Cadas H, Schinelli S, Piomelli D (1996b) Membrane localization of N-acylphosphatidylethanolamine in central neurons: studies with exogenous phospholipases. J Lipid Mediat Cell Signal 14:63–70PubMedGoogle Scholar
  17. Carrier EJ, Kearn CS, Barkmeier AJ et al. (2004) Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65:999–1007PubMedGoogle Scholar
  18. Chen P, Hu S, Yao J et al. (2005) Induction of cyclooxygenase-2 by anandamide in cerebral microvascular endothelium. Microvasc Res 69:28–35PubMedGoogle Scholar
  19. Craib SJ, Ellington HC, Pertwee RG et al. (2001) A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus. Br J Pharmacol 134:30–37PubMedGoogle Scholar
  20. Cravatt BF, Giang DK, Mayfield SP et al. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384:83–87PubMedGoogle Scholar
  21. Dawson RMC, Clarke N, Quarles RH (1969) N-acylphosphatidylethanolamine, a phospholipid that is rapidly metabolized during the early germination of pea seeds. Biochem J 114:265–267PubMedGoogle Scholar
  22. De Petrocellis L, Melck D, Ueda N et al. (1997) Novel inhibitors of brain, neuronal, and basophilic anandamide amidohydrolase. Biochem Biophys Res Commun 231:82–88PubMedGoogle Scholar
  23. Devane WA, Hanus L, Breuer A et al. (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedGoogle Scholar
  24. Di Marzo V, Fontana A, Cadas H et al. (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372:686–691PubMedGoogle Scholar
  25. Di Marzo V, Bisogno T, Sugiura T et al. (1998) The novel endogenous cannabinoid 2-arachidonoylglycerol is inactivated by neuronal- and basophil-like cells: connections with anandamide. Biochem J 331:15–19PubMedGoogle Scholar
  26. Diana MA, Marty A (2004) Endocannabinoid-mediated short-term synaptic plasticity: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). Br J Pharmacol 142:9–19PubMedGoogle Scholar
  27. Dinh TP, Carpenter D, Leslie FM et al. (2002) Brain monoglyceride lipase participating in endocannabinoid inactivation. Proc Natl Acad Sci USA 99:10819–10824PubMedGoogle Scholar
  28. Dinh TP, Kathuria S, Piomelli D (2004) RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol Pharmacol 66:1260–1264PubMedGoogle Scholar
  29. Duncan M, Thomas AD, Cluny NL et al. (2008) Distribution and function of monoacylglycerol lipase in the gastrointestinal tract. Am J Physiol – Gastrointest Liver Physiol 295:G1255–G1265PubMedGoogle Scholar
  30. Edgemond WS, Hillard CJ, Falck JR et al. (1998) Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonylethanolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol Pharmacol 54:180–188PubMedGoogle Scholar
  31. Edwards DA, Kim J, Alger BE (2006) Multiple mechanisms of endocannabinoid response initiation in hippocampus. J Neurophysiol 95:67–75PubMedGoogle Scholar
  32. Egertova M, Simon GM, Cravatt BF et al. (2008) Localization of N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) expression in mouse brain: A new perspective on N-acylethanolamines as neural signaling molecules. J Comp Neurol 506:604–615PubMedGoogle Scholar
  33. Egertová M, Giang DK, Cravatt BF et al. (1998) A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc R Soc Lond B Biol Sci 265:2081–2085Google Scholar
  34. Fowler CJ (2007) The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action. Br J Pharmacol 152:594–601PubMedGoogle Scholar
  35. Fowler CJ, Tiger G, Stenstrom A (1997) Ibuprofen inhibits rat brain deamidation of anandamide at pharmacologically relevant concentrations. Mode of inhibition and structure–activity relationship. J Pharmacol Exp Ther 283:729–734PubMedGoogle Scholar
  36. Fowler CJ, Janson U, Johnson RM et al. (1999) Inhibition of anandamide hydrolysis by the enantiomers of ibuprofen, ketorolac, and flurbiprofen. Arch Biochem Biophys 362:191–196PubMedGoogle Scholar
  37. Fowler CJ, Holt S, Tiger G (2003) Acidic nonsteroidal anti-inflammatory drugs inhibit rat brain fatty acid amide hydrolase in a pH-dependent manner. J Enzyme Inhib Med Chem 18:55–58PubMedGoogle Scholar
  38. Fu J, Kim J, Oveisi F et al. (2008) Targeted enhancement of oleoylethanolamide production in proximal small intestine induces across-meal satiety in rats. Am J Physiol Regul Integr Comp Physiol 295:R45–R50PubMedGoogle Scholar
  39. Gerdeman GL, Lovinger DM (2003) Emerging roles for endocannabinoids in long-term synaptic plasticity. Br J Pharmacol 140(5):781–789PubMedGoogle Scholar
  40. Ghafouri N, Tiger G, Razdan RK et al. (2004) Inhibition of monoacylglycerol lipase and fatty acid amide hydrolase by analogues of 2-arachidonoylglycerol. Br J Pharmacol 143:774–784PubMedGoogle Scholar
  41. Gillett MP, Vieira EM, Dimenstein R (1993) The phospholipase activities present in preheparin mouse plasma are inhibited by antiserum to hepatic lipase. Int J Biochem 25:449–453PubMedGoogle Scholar
  42. Gillum MP, Zhang D, Zhang XM et al. (2008) N-acylphosphatidylethanolamine, a gut-derived circulating factor induced by fat ingestion, inhibits food intake. Cell 135:813–824PubMedGoogle Scholar
  43. Glass M, Hong JW, Sato TA et al. (2005) Misidentification of prostamides as prostaglandins. J Lipid Res 46:1364–1368PubMedGoogle Scholar
  44. Gobbi G, Bambico FR, Mangieri R et al. (2005) Antidepressant-like activity and modulation of brain monoaminergic transmission by blockade of anandamide hydrolysis. Proc Natl Acad Sci USA 102:18620–18625PubMedGoogle Scholar
  45. Goding JW, Grobben B, Slegers H (2003) Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Biochim Biophys Acta – Mol Basis Dis 1638:1–19Google Scholar
  46. Goparaju SK, Ueda N, Yamaguchi H et al. (1998) Anandamide amidohydrolase reacting with 2-arachidonoylglycerol, another cannabinoid receptor ligand. FEBS Lett 422:69–73PubMedGoogle Scholar
  47. Grazia Cascio M, Minassi A, Ligresti A et al. (2004) A structure–activity relationship study on N-arachidonoyl-amino acids as possible endogenous inhibitors of fatty acid amide hydrolase. Biochem Biophys Res Commun 314:192–196PubMedGoogle Scholar
  48. Hada T, Hagiya H, Suzuki H et al. (1994) Arachidonate 12-lipoxygenase of rat pineal glands: catalytic properties and primary structure deduced from its cDNA. Biochim Biophys Acta 1211:221–228PubMedGoogle Scholar
  49. Hampson AJ, Hill WAG, Zanphillips M et al. (1995) Anandamide hydroxylation by brain lipoxygenase: metabolite structures and potencies at the cannabinoid receptor. Biochim Biophys Acta – Lip Lip Met 1259:173–179Google Scholar
  50. Hansen HS, Lauritzen L, Strand AM et al. (1995) Glutamate stimulates the formation of N-acylphosphatidylethanolamine and N-acylethanolamine in cortical neurons in culture. Biochim Biophys Acta – Lip Lip Met 1258:303–308Google Scholar
  51. Hanus L, Gopher A, Almog S et al. (1993) Two new unsaturated fatty acid ethanolamides in brain that bind to the cannabinoid receptor. J Med Chem 36:3032–3034PubMedGoogle Scholar
  52. Hashimotodani Y, Ohno-Shosaku T, Maejima T et al. (2008) Pharmacological evidence for the involvement of diacylglycerol lipase in depolarization-induced endocanabinoid release. Neuropharmacol 54:58–67Google Scholar
  53. Higgs HN, Glomset JA (1994) Identification of a phosphatidic acid-preferring phospholipase A1 from bovine brain and testis. Proc Natl Acad Sci USA 91:9574–9578PubMedGoogle Scholar
  54. Higgs HN, Han MH, Johnson GE et al. (1998) Cloning of a phosphatidic acid-preferring phospholipase A1 from bovine testis. J Biol Chem 273:5468–5477PubMedGoogle Scholar
  55. Hiramatsu T, Sonoda H, Takanezawa Y et al. (2003) Biochemical and molecular characterization of two phosphatidic acid-selective phospholipase A1s, mPA-PLA1α and mPA-PLA1β. J Biol Chem 278:49438–49447PubMedGoogle Scholar
  56. Hirasawa K, Irvine RF, Dawson RMC (1981) The catabolism of phosphatidylinositol by an EDTA-insensitive phospholipase A1 and calcium-dependent phosphatidylinositol phosphodiesterase in rat brain. Eur J Biochem 120:53–58PubMedGoogle Scholar
  57. Ho W-SV, Randall MD (2007) Endothelium-dependent metabolism by endocannabinoid hydrolases and cyclooxygenases limits vasorelaxation to anandamide and 2-arachidonoylglycerol. Br J Pharmacol 150:641–651PubMedGoogle Scholar
  58. Hohmann AG, Suplita RL, Bolton NM et al. (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112PubMedGoogle Scholar
  59. Hoover HS, Blankman JL, Niessen S et al. (2008) Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling. Bioorg Med Chem Lett 18:5838–5841PubMedGoogle Scholar
  60. Hu SSJ, Bradshaw HB, Chen JSC et al. (2008) Prostaglandin E-2 glycerol ester, an endogenous COX-2 metabolite of 2-arachidonoylglycerol, induces hyperalgesia and modulates NFκB activity. Br J Pharmacol 153:1538–1549PubMedGoogle Scholar
  61. Inoue M, Okuyama H (1984) Phospholipase A1 acting on phosphatidic acid in porcine platelet membranes. J Biol Chem 259:5083–5086PubMedGoogle Scholar
  62. Jaye M, Lynch KJ, Krawiec J et al. (1999) A novel endothelial-derived lipase that modulates HDL metabolism. Nat Genet 21:424–428PubMedGoogle Scholar
  63. Jhaveri MD, Richardson D, Robinson I et al. (2008) Inhibition of fatty acid amide hydrolase and cycloxygenase-2 increases levels of endocannabinoids and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacol 55:85–93Google Scholar
  64. Jimenez-Monreal AM, Villalain J, Aranda FJ et al. (1998) The phase behavior of aqueous dispersions of unsaturated mixtures of diacylglycerols and phospholipids. Biochim Biophys Acta 1373:209–219PubMedGoogle Scholar
  65. Jin XH, Okamoto Y, Morishita J et al. (2007) Discovery and characterization of a Ca2+-independent phosphatidylethanolamine N-acyltransferase generating the anandamide precursor and its congeners. J Biol Chem 282:3614–3623PubMedGoogle Scholar
  66. Karbarz MJ, Luo L, Chang L et al. (2009) Biochemical and biological properties of 4-(3-phenyl-[1, 2, 4] thiadiazol-5-yl)-piperazine-1-carboxylic acid phenylamide, a mechanism-based inhibitor of fatty acid amide hydrolase. Anesth Analg 108:316–329PubMedGoogle Scholar
  67. Kathuria S, Gaetani S, Fegley D et al. (2003) Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med 9:76–81PubMedGoogle Scholar
  68. Kim J, Alger BE (2004) Inhibition of cyclooxygenase-2 potentiates retrograde endocannabinoid effects in hippocampus. Nat Neurosci 7:697–698PubMedGoogle Scholar
  69. Kim J, Isokawa M, Ledent C et al. (2002) Activation of muscarinic acetylcholine receptors enhances the release of endogenous cannabinoids in the hippocampus. J Neurosci 22:10182–10191PubMedGoogle Scholar
  70. Kobayashi T, Kishimoto M, Okuyama H (1996) Phospholipases involved in lysophosphatidylinositol metabolism in rat brain. J Lipid Mediat Cell Signal 14:33–37PubMedGoogle Scholar
  71. Kohno M, Hasegawa H, Inoue A et al. (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun 347:827–832PubMedGoogle Scholar
  72. Koutek B, Prestwich GD, Howlett AC et al. (1994) Inhibitors of arachidonoyl ethanolamide hydrolysis. J Biol Chem 269:22937–22940PubMedGoogle Scholar
  73. Kozak KR, Rowlinson SW, Marnett LJ (2000) Oxygenation of the endocannabinoid, 2-arachidonylglycerol, to glyceryl prostaglandins by cyclooxygenase-2. J Biol Chem 275:33744–33749PubMedGoogle Scholar
  74. Kozak KR, Crews BC, Ray JL et al. (2001) Metabolism of prostaglandin glycerol esters and prostaglandin ethanolamides in vitro and in vivo. J Biol Chem 276:36993–36998PubMedGoogle Scholar
  75. Kozak KR, Gupta RA, Moody JS et al. (2002) 15-lipoxygenase metabolism of 2-arachidonylglycerol: Generation of a PPARα agonist. J Biol Chem 277:23278–23286PubMedGoogle Scholar
  76. Kreitzer AC, Regehr WG (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29:717–727PubMedGoogle Scholar
  77. Kucera GL, Sisson PJ, Thomas MJ et al. (1988) On the substrate specificity of rat liver phospholipase A1. J Biol Chem 263:1920–1928PubMedGoogle Scholar
  78. Lee MW, Kraemer FB, Severson DL (1995) Characterization of a partially purified diacylglycerol lipase from bovine aorta. Biochim Biophys Acta 1254:311–318PubMedGoogle Scholar
  79. Leung D, Saghatelian A, Simon GM et al. (2006) Inactivation of N-acyl phosphatidylethanolamine phospholipase D reveals multiple mechanisms for the biosynthesis of endocannabinoids. Biochemistry 45:4720–4726PubMedGoogle Scholar
  80. Lichtman AH, Hawkins EG, Griffin G et al. (2002) Pharmacological activity of fatty acid amides is regulated, but not mediated, by fatty acid amide hydrolase in vivo. J Pharmacol Exp Ther 302:73–79PubMedGoogle Scholar
  81. Liu Q, Tonai T, Ueda N (2002) Activation of N-acylethanolamine-releasing phospholipase D by polyamines. Chem Phys Lipids 115:77–84PubMedGoogle Scholar
  82. Liu J, Wang L, Harvey-White J et al. (2008) Multiple pathways involved in the biosynthesis of anandamide. Neuropharmacol 54:1–7Google Scholar
  83. Long JZ, Li W, Booker L et al. (2009) Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol 5:37–44PubMedGoogle Scholar
  84. Makara JK, Mor M, Fegley D et al. (2005) Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci 8:1139–1141PubMedGoogle Scholar
  85. Makara JK, Mor M, Fegley D et al. (2007) Selective inhibition of 2-AG hydrolysis enhances endocannabinoid signaling in hippocampus. Nat Neurosci 10(1):134Google Scholar
  86. Millns PJ, Chapman V, Kendall DA (2001) Cannabinoid inhibition of the capsaicin-induced calcium response in rat dorsal root ganglion neurones. Br J Pharmacol 132:969–971PubMedGoogle Scholar
  87. Moise AM, Eisenstein SA, Astarita G et al. (2008) An endocannabinoid signaling system modulates anxiety-like behavior in male Syrian hamsters. Psychopharmacol 200:333–346Google Scholar
  88. Moody JS, Kozak KR, Ji C et al. (2001) Selective oxygenation of the endocannabinoid 2-arachidonylglycerol by leukocyte-type 12-lipoxygenase. Biochemistry 40:861–866PubMedGoogle Scholar
  89. Mulder AM, Cravatt BF (2006) Endocannabinoid metabolism in the absence of fatty acid amide hydrolase (FAAH): discovery of phosphorylcholine derivatives of N-acyl ethanolamines. Biochemistry 45:11267–11277PubMedGoogle Scholar
  90. Nakane S, Oka S, Arai S et al. (2002) 2-Arachidonoyl-sn-glycero-3-phosphate, an arachidonic acid-containing lysophosphatidic acid: occurrence and rapid enzymatic conversion to 2-arachidonoyl-sn-glycerol, a cannabinoid receptor ligand, in rat brain. Arch Biochem Biophys 402:51–58PubMedGoogle Scholar
  91. Natarajan V, Reddy PV, Schmid PC et al. (1982) N-Acylation of ethanolamine phospholipids in canine myocardium. Biochim Biophys Acta 712:342–355PubMedGoogle Scholar
  92. Natarajan V, Schmid PC, Reddy PV et al. (1984) Catabolism of N-acylethanolamine phospholipids by dog brain preparations. J Neurochem 42:1613–1619PubMedGoogle Scholar
  93. Niforatos W, Zhang X-F, Lake MR et al. (2007) Activation of TRPA1 channels by the fatty acid amide hydrolase inhibitor 3'-carbamoylbiphenyl-3-yl cyclohexylcarbamate (URB597). Mol Pharmacol 71:1209–1216PubMedGoogle Scholar
  94. Nishiyama M, Watanabe T, Ueda N et al. (1993) Arachidonate 12-lipoxygenase is localized in neurons, glial cells, and endothelial cells of the canine brain. J Histochem Cytochem 41:111–117PubMedGoogle Scholar
  95. Oka S, Tsuchie A, Tokumura A et al. (2003) Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species. J Neurochem 85:1374–1381PubMedGoogle Scholar
  96. Oka S, Arai S, Waku K et al. (2007a) Depolarization-induced rapid generation of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand, in rat brain synaptosomes. J Biochem 141:687–697PubMedGoogle Scholar
  97. Oka S, Nakajima K, Yamashita A et al. (2007b) Identification of GPR55 as a lysophosphatidylinositol receptor. Biochem Biophys Res Commun 362:928–934PubMedGoogle Scholar
  98. Oka S, Toshida T, Maruyama K et al. (2009) 2-Arachidonoyl-sn-glycero-3-phosphoinositol: A Possible Natural Ligand for GPR55. J Biochem 145:13–20PubMedGoogle Scholar
  99. Okamoto Y, Morishita J, Tsuboi K et al. (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305PubMedGoogle Scholar
  100. Overton HA, Babbs AJ, Doel SM et al. (2006) Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab 3:167–175PubMedGoogle Scholar
  101. Parrish JC, Nichols DE (2006) Serotonin 5-HT2A receptor activation induces 2-arachidonoylglycerol release through a phospholipase C-dependent mechanism. J Neurochem 99:1164–1175PubMedGoogle Scholar
  102. Patsos HA, Hicks DJ, Dobson RR et al. (2005) The endogenous cannabinoid, anandamide, induces cell death in colorectal carcinoma cells: a possible role for cyclooxygenase-2. Gut 54:1741–1750PubMedGoogle Scholar
  103. Petersen G, Hansen HS (1999) N-acylphosphatidylethanolamine-hydrolysing phospholipase D lacks the ability to transphosphatidylate. FEBS Lett 455:41–44PubMedGoogle Scholar
  104. Reddy PV, Natarajan V, Schmid PC et al. (1983) N-Acylation of dog heart ethanolamine phospholipids by transacylase activity. Biochim Biophys Acta – Lip Lip Met 750:472–480Google Scholar
  105. Rindlisbacher B, Reist M, Zahler P (1987) Diacylglycerol breakdown in plasma membranes of bovine chromaffin cells is a two-step mechanism mediated by a diacylglycerol lipase and a monoacylglycerol lipase. Biochim Biophys Acta 905:349–357PubMedGoogle Scholar
  106. Rockwell CE, Raman P, Kaplan BLF et al. (2008) A COX-2 metabolite of the endogenous cannabinoid, 2-arachidonyl glycerol, mediates suppression of IL-2 secretion in activated Jurkat T cells. Biochem Pharmacol 76:353–361PubMedGoogle Scholar
  107. Russo R, LoVerme J, La Rana G et al. (2007) The fatty-acid amide hydrolase inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J Pharmacol Exp Ther 322:236–242PubMedGoogle Scholar
  108. Saario SM, Savinainen JR, Laitinen JT et al. (2004) Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2-arachidonoylglycerol in rat cerebellar membranes. Biochem Pharmacol 67:1381–1387PubMedGoogle Scholar
  109. Sakagami H, Aoki J, Natori Y et al. (2005) Biochemical and molecular characterization of a novel choline-specific glycerophosphodiester phosphodiesterase belonging to the nucleotide pyrophosphatase/phosphodiesterase family. J Biol Chem 280:23084–23093PubMedGoogle Scholar
  110. Sang N, Zhang J, Chen C (2006) PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons. J Physiol 572:735–745PubMedGoogle Scholar
  111. Sang N, Zhang J, Chen C (2007) COX-2 oxidative metabolite of endocannabinoid 2-AG enhances excitatory glutamatergic synaptic transmission and induces neurotoxicity. J Neurochem 102:1966–1977PubMedGoogle Scholar
  112. Sarmad S, Patel A, Barrett DA et al. (2008) Calcium-independent formation of endocannabinoids in rat brain slices. Proceedings of the British Pharmacological Society, p 111PGoogle Scholar
  113. Sato T, Aoki J, Nagai Y et al. (1997) Serine phospholipid-specific phospholipase A that is secreted from activated platelets. A new member of the lipase family. J Biol Chem 272:2192–2198PubMedGoogle Scholar
  114. Schmid PC, Reddy PV, Natarajan V et al. (1983) Metabolism of N-acylethanolamine phospholipids by a mammalian phosphodiesterase of the phospholipase D type. J Biol Chem 258:9302–9306PubMedGoogle Scholar
  115. Simon GM, Cravatt BF (2006) Endocannabinoid biosynthesis proceeding through glycerophospho-N-acyl ethanolamine and a role for α/β hydrolase 4 in this pathway. J Biol Chem 281:26465–26472PubMedGoogle Scholar
  116. Simon GM, Cravatt BF (2008) Anandamide biosynthesis catalyzed by the phosphodiesterase GDE1 and detection of glycerophospho-n-acyl ethanolamine precursors in mouse brain. J Biol Chem 283:9341–9349PubMedGoogle Scholar
  117. Snider NT, Kornilov AM, Kent UM et al. (2007) Anandamide metabolism by human liver and kidney microsomal cytochrome P450 enzymes to form hydroxyeicosatetraenoic and epoxyeicosatrienoic acid ethanolamides. J Pharmacol Exp Ther 321:590–597PubMedGoogle Scholar
  118. Snider NT, Sikora MJ, Sridar C et al. (2008) The endocannabinoid anandamide is a substrate for the human polymorphic cytochrome P450 2D6. J Pharmacol Exp Ther 327:538–545PubMedGoogle Scholar
  119. Stark K, Dostalek M, Guengerich FP (2008) Expression and purification of orphan cytochrome P450 4X1 and oxidation of anandamide. FEBS J 275:3706–3717PubMedGoogle Scholar
  120. Stella N, Piomelli D (2001) Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur J Pharmacol 425:189–196PubMedGoogle Scholar
  121. Stella N, Schweitzer P, Piomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature 388:773–778PubMedGoogle Scholar
  122. Sugiura T, Waku K (2000) 2-Arachidonoylglycerol and the cannabinoid receptors. pp. 89-106.Google Scholar
  123. Sugiura T, Waku K (2002) Cannabinoid receptors and their endogenous ligands. J Biochem 132:7–12PubMedGoogle Scholar
  124. Sugiura T, Kondo S, Sukagawa A et al. (1996) Transacylase-mediated and phosphodiesterase-mediated synthesis of N-arachidonoylethanolamine, an endogenous cannabinoid receptor ligand, in rat brain microsomes: comparison with synthesis from free arachidonic acid and ethanolamine. Eur J Biochem 240:53–62PubMedGoogle Scholar
  125. Sugiura T, Kodaka T, Kondo S et al. (1997) Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor? Structural requirements for triggering a Ca2+ transient in NG108-15 cells. J Biochem (Tokyo) 122:890–895Google Scholar
  126. Sugiura T, Kodaka T, Nakane S et al. (1999) Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure–activity relationship of 2-arachidonoylglycerol ether-linked analogues, and related compounds. J Biol Chem 274:2794–2801PubMedGoogle Scholar
  127. Suh PG, Park JI, Manzoli L et al. (2008) Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB Rep 41(6):415–434PubMedGoogle Scholar
  128. Sun YX, Tsuboi K, Okamoto Y et al. (2004) Biosynthesis of anandamide and N-palmitoylethanolamine by sequential actions of phospholipase A2 and lysophospholipase D. Biochem J 380:749–756PubMedGoogle Scholar
  129. Sun YX, Tsuboi K, Zhao LY et al. (2005) Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages. Biochim Biophys Acta 1736:211–220PubMedGoogle Scholar
  130. Sutherland CA, Amin D (1982) Relative activities of rat and dog platelet phospholipase A2 and diglyceride lipase. Selective inhibition of diglyceride lipase by RHC 80267. J Biol Chem 257:14006–14010Google Scholar
  131. Szabo B, Urbanski MJ, Bisogno T et al. (2006) Depolarization-induced retrograde synaptic inhibition in the mouse cerebellar cortex is mediated by 2-arachidonoylglycerol. J Physiol 577:263–280PubMedGoogle Scholar
  132. Tian XY, Guo JX, Yao FM et al. (2005) The conformation, location, and dynamic properties of the endocannabinoid ligand anandamide in a membrane bilayer. J Biol Chem 280:29788–29795PubMedGoogle Scholar
  133. Tornqvist H, Belfrage P (1976) Purification and some properties of a monoacylglycerol-hydrolyzing enzyme of rat adipose tissue. J Biol Chem 251:813–819PubMedGoogle Scholar
  134. Tsou K, Nogueron MI, Muthian S et al. (1998) Fatty acid amide hydrolase is located preferentially in large neurons in the rat central nervous system as revealed by immunohistochemistry. Neurosci Lett 254:137–140PubMedGoogle Scholar
  135. Tsuboi K, Hilligsmann C, Vandevoorde S et al. (2004) N-cyclohexanecarbonylpentadecylamine: a selective inhibitor of the acid amidase hydrolysing N-acylethanolamines, as a tool to distinguish acid amidase from fatty acid amide hydrolase. Biochem J 379:99–106PubMedGoogle Scholar
  136. Tsuboi K, Sun YX, Okamoto Y et al. (2005) Molecular characterization of N-acylethanolamine-hydrolyzing acid amidase, a novel member of the choloylglycine hydrolase family with structural and functional similarity to acid ceramidase. J Biol Chem 280:11082–11092PubMedGoogle Scholar
  137. Tsutsumi T, Kobayashi T, Ueda H et al. (1994) Lysophosphoinositide-specific phospholipase C in rat brain synaptic plasma membranes. Neurochem Res 19:399–406PubMedGoogle Scholar
  138. Tsutsumi T, Kobayashi T, Miyashita M et al. (1995) A lysophosphoinositide-specific phospholipase C distinct from other phospholipase C families in rat brain. Arch Biochem Biophys 317:331–336PubMedGoogle Scholar
  139. Ueda H, Kobayashi T, Kishimoto M et al. (1993a) A possible pathway of phosphoinositide metabolism through EDTA-insensitive phospholipase A1 followed by lysophosphoinositide-specific phospholipase C in rat brain. J Neurochem 61:1874–1881PubMedGoogle Scholar
  140. Ueda H, Kobayashi T, Kishimoto M et al. (1993b) The presence of Ca2+-independent phospholipase A1 highly specific for phosphatidylinositol in bovine brain. Biochem Biophys Res Commun 195:1272–1279PubMedGoogle Scholar
  141. Ueda N, Yamamoto K, Yamamoto S et al. (1995) Lipoxygenase-catalyzed oxygenation of arachidonylethanolamide, a cannabinoid receptor agonist. Biochim Biophys Acta – Lip Lip Met 1254:127–134Google Scholar
  142. Ueda N, Yamanaka K, Terasawa Y et al. (1999) An acid amidase hydrolyzing anandamide as an endogenous ligand for cannabinoid receptors. FEBS Lett 454:267–270PubMedGoogle Scholar
  143. van der Stelt M, Trevisani M, Vellani V et al. (2005) Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J 24:3026–3037PubMedGoogle Scholar
  144. Van Zadelhoff G, Veldink GA, Vliegenthart JFG (1998) With anandamide as substrate plant 5-lipoxygenases behave like 11-lipoxygenases. Biochem Biophys Res Commun 248:33–38PubMedGoogle Scholar
  145. Vandevoorde S, Saha B, Mahadevan A et al. (2005) Influence of the degree of unsaturation of the acyl side chain upon the interaction of analogues of 1-arachidonoylglycerol with monoacylglycerol lipase and fatty acid amide hydrolase. Biochem Biophys Res Commun 337:104–109PubMedGoogle Scholar
  146. Vandevoorde S, Jonsson KO, Labar G et al. (2007) Lack of selectivity of URB602 for 2-oleoylglycerol compared to anandamide hydrolysis in vitro. Br J Pharmacol 150:186–191PubMedGoogle Scholar
  147. Varma N, Carlson GC, Ledent C et al. (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J Neurosci 21:RC133Google Scholar
  148. Veldhuis WB, van der Stelt M, Wadman MW et al. (2003) Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: Role of vanilloid receptors and lipoxygenases. J Neurosci 23:4127–4133PubMedGoogle Scholar
  149. Vellani V, Petrosino S, De Petrocellis L et al. (2008) Functional lipidomics. Calcium-independent activation of endocannabinoid/endovanilloid lipid signalling in sensory neurons by protein kinases C and A and thrombin. Neuropharmacol 55:1274–1279Google Scholar
  150. Vila A, Rosengarth A, Piomelli D et al. (2007) Hydrolysis of prostaglandin glycerol esters by the endocannabinoid-hydrolyzing enzymes, monoacylglycerol lipase and fatty acid amide hydrolase. Biochemistry 46:9578–9585PubMedGoogle Scholar
  151. Walter L, Dinh T, Stella N (2004) ATP induces a rapid and pronounced increase in 2-arachidonoylglycerol production by astrocytes, a response limited by monoacylglycerol lipase. J Neurosci 24:8068–8074PubMedGoogle Scholar
  152. Wang J, Okamoto Y, Morishita J et al. (2006) Functional analysis of the purified anandamide-generating phospholipase D as a member of the metallo-β-lactamase family. J Biol Chem 281:12325–12335PubMedGoogle Scholar
  153. Wang J, Okamoto Y, Tsuboi K et al. (2008a) The stimulatory effect of phosphatidylethanolamine on N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD). Neuropharmacol 54:8–15Google Scholar
  154. Wang J, Zhao LY, Uyama T et al. (2008b) Amino acid residues crucial in pH regulation and proteolytic activation of N-acylethanolamine-hydrolyzing acid amidase. Biochim Biophys Acta 1781:710–717PubMedGoogle Scholar
  155. Wei BQ, Mikkelsen TS, McKinney MK et al. (2006) A second fatty acid amide hydrolase with variable distribution among placental mammals. J Biol Chem 281:36569–36578PubMedGoogle Scholar
  156. Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588–592PubMedGoogle Scholar
  157. Wilson RI, Kunos G, Nicoll RA (2001) Presynaptic specificity of endocannabinoid signaling in the hippocampus. Neuron 31:453–462PubMedGoogle Scholar
  158. Woodward DF, Carling RW, Cornell CL et al. (2008) The pharmacology and therapeutic relevance of endocannabinoid derived cyclo-oxygenase (COX)-2 products. Phamacol Ther 120(1):71–80Google Scholar
  159. Yoshida T, Hashimoto K, Zimmer A et al. (2002) The cannabinoid CB1 receptor mediates retrograde signals for depolarization-induced suppression of inhibition in cerebellar Purkinje cells. J Neurosci 22:1690–1697PubMedGoogle Scholar
  160. Yu M, Ives D, Ramesha CS (1997) Synthesis of prostaglandin E2 ethanolamide from anandamide by cyclooxygenase-2. J Biol Chem 272:21181–21186PubMedGoogle Scholar
  161. Zhang D, Saraf A, Kolasa T et al. (2007) Fatty acid amide hydrolase inhibitors display broad selectivity and inhibit multiple carboxylesterases as off-targets. Neuropharmacol 52:1095–1105Google Scholar
  162. Zheng B, Chen D, Farquhar MG (2000) MIR16, a putative membrane glycerophosphodiester phosphodiesterase, interacts with RGS16. Proc Natl Acad Sci USA 97:3999–4004PubMedGoogle Scholar
  163. Zheng B, Berrie CP, Corda D et al. (2003) GDE1/MIR16 is a glycerophosphoinositol phosphodiesterase regulated by stimulation of G protein-coupled receptors. Proc Natl Acad Sci USA 100:1745–1750PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  1. 1.School of Biomedical Sciences and Institute of NeuroscienceUniversity of Nottingham Medical SchoolNottinghamUK

Personalised recommendations