Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain

Diacylglycerol (DAG) lipase activity is required for axonal growth during development and for retrograde synaptic signaling at mature synapses. This enzyme synthesizes the endocannabinoid 2-arachidonoyl-glycerol (2-AG), and the CB1 cannabinoid receptor is also required for the above responses. We now report on the cloning and enzymatic characterization of the first specific sn-1 DAG lipases. Two closely related genes have been identified and their expression in cells correlated with 2-AG biosynthesis and release. The expression of both enzymes changes from axonal tracts in the embryo to dendritic fields in the adult, and this correlates with the developmental change in requirement for 2-AG synthesis from the pre- to the postsynaptic compartment. This switch provides a possible explanation for a fundamental change in endocannabinoid function during brain development. Identification of these enzymes may offer new therapeutic opportunities for a wide range of disorders.

[1]  J. Silver,et al.  Fibroblast Growth Factor Receptor Function Is Required for the Orderly Projection of Ganglion Cell Axons in the Developing Mammalian Retina , 1996, Molecular and Cellular Neuroscience.

[2]  N. Cairns,et al.  The quantification of gene expression in an animal model of brain ischaemia using TaqMan real-time RT-PCR. , 2002, Brain research. Molecular brain research.

[3]  D. Severson,et al.  Characterization of a partially purified diacylglycerol lipase from bovine aorta. , 1995, Biochimica et biophysica acta.

[4]  F. Walsh,et al.  The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response , 2003, The Journal of cell biology.

[5]  References , 1971 .

[6]  L. Petrocellis,et al.  Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action , 1998, Trends in Neurosciences.

[7]  J. Brotchie,et al.  Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of Parkinson's disease , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  W. Zieglgänsberger,et al.  The endogenous cannabinoid system controls extinction of aversive memories , 2002, Nature.

[9]  Anatol C. Kreitzer,et al.  Retrograde Inhibition of Presynaptic Calcium Influx by Endogenous Cannabinoids at Excitatory Synapses onto Purkinje Cells , 2001, Neuron.

[10]  R. Pertwee.  Pharmacology of cannabinoid CB1 and CB2 receptors. , 1997, Pharmacology & therapeutics.

[11]  K. Waku,et al.  2‐Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+‐dependent and ‐independent mechanisms , 1998, FEBS letters.

[12]  A. Yamashita,et al.  2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. , 1995, Biochemical and biophysical research communications.

[13]  K. Mackie,et al.  Short-Term Retrograde Inhibition of GABAergic Synaptic Currents in Rat Purkinje Cells Is Mediated by Endogenous Cannabinoids , 2002, The Journal of Neuroscience.

[14]  D. Piomelli,et al.  A second endogenous cannabinoid that modulates long-term potentiation , 1997, Nature.

[15]  R. Nicoll,et al.  Endocannabinoid Signaling in the Brain , 2002, Science.

[16]  Z. Vogel,et al.  Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. , 1995, Biochemical pharmacology.

[17]  J. Morisset,et al.  Endogenous Arachidonic Acid Release and Pancreatic Amylase Secretion , 1997, Pancreas.

[18]  S. Ben-Shabat,et al.  An endogenous cannabinoid (2-AG) is neuroprotective after brain injury , 2001, Nature.

[19]  R. Palmiter,et al.  Leptin-regulated endocannabinoids are involved in maintaining food intake , 2001, Nature.

[20]  Yamaguchi Shotaro,et al.  Cloning and structure of the mono- and diacylglycerol lipase-encoding gene from Penicillium camembertii U-150. , 1991 .

[21]  L. Petrocellis,et al.  Biosynthesis, release and degradation of the novel endogenous cannabimimetic metabolite 2-arachidonoylglycerol in mouse neuroblastoma cells. , 1997, The Biochemical journal.