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A Key Role for Diacylglycerol Lipase- in Metabotropic Glutamate Receptor-Dependent Endocannabinoid Mobilization

Departments of Pharmacology (K.-M.J., G.A., D.P.) and Biological Chemistry (C.Z., D.P.), University of California, Irvine, California; Department of Drug Discovery and Development, Italian Institute of Technology, Genova, Italy (D.P.); and Department of Anesthesiology, University of Washington, Seattle, Washington (M.W., K.M.)

Activation of group I metabotropic glutamate (mGlu) receptors recruits the endocannabinoid system to produce both short- and long-term changes in synaptic strength in many regions of the brain. Although there is evidence that the endocannabinoid 2-arachidonoylglycerol (2-AG) mediates this process, the molecular mechanism underlying 2-AG mobilization remains unclear. In the present study, we used a combination of genetic and targeted lipidomic approaches to investigate the role of the postsynaptic membrane-associated lipase, diacylglycerol lipase type- (DGL-), in mGlu receptor-dependent 2-AG mobilization. DGL- overexpression in mouse neuroblastoma Neuro-2a cells increased baseline 2-AG levels. This effect was accompanied by enhanced utilization of the 2-AG precursor 1-stearoyl,2-arachidonoyl-sn-glycerol and increased accumulation of the 2-AG breakdown product arachidonic acid. A similar, albeit less marked response was observed with other unsaturated and polyunsaturated monoacylglycerols, 1,2-diacylglycerols, and fatty acids. Silencing of DGL- by RNA interference elicited lipidomic changes opposite those of DGL- overexpression and abolished group I mGlu receptor-dependent 2-AG mobilization. Coimmunoprecipitation and site-directed mutagenesis experiments revealed that DGL- interacts, via a PPxxF domain, with the coiled-coil (CC)-Homer proteins Homer-1b and Homer-2, two components of the molecular scaffold that enables group I mGlu signaling. DGL- mutants that do not bind Homer maintained their ability to generate 2-AG in intact cells but failed to associate with the plasma membrane. The findings indicate that DGL- mediates group I mGlu receptor-induced 2-AG mobilization. They further suggest that the interaction of CC-Homer with DGL- is necessary for appropriate function of this lipase.

Address correspondence to: Dr. Daniele Piomelli, Department of Pharmacology, 3101 Gillespie NRF, University of California, Irvine, CA 92697-4625. E-mail: piomelli{at}uci.edu

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