QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: mol.107.037796v1 72/3/612    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jung, K.-M. Articles by Piomelli, D. Search for Related Content PubMed PubMed Citation Articles by Jung, K.-M. Articles by Piomelli, D.

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.

Received for publication May 4, 2007.

Accepted for publication June 21, 2007.

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

This article has been cited by other articles:

				Y.-J. Won, H. L. Puhl III, and S. R. Ikeda Molecular Reconstruction of mGluR5a-Mediated Endocannabinoid Signaling Cascade in Single Rat Sympathetic Neurons J. Neurosci., October 28, 2009; 29(43): 13603 - 13612. [Abstract] [Full Text] [PDF]

				S.-y. Zhang, M. Xu, Q.-l. Miao, M.-m. Poo, and X.-h. Zhang Endocannabinoid-Dependent Homeostatic Regulation of Inhibitory Synapses by Miniature Excitatory Synaptic Activities J. Neurosci., October 21, 2009; 29(42): 13222 - 13231. [Abstract] [Full Text] [PDF]

				M. Kano, T. Ohno-Shosaku, Y. Hashimotodani, M. Uchigashima, and M. Watanabe Endocannabinoid-Mediated Control of Synaptic Transmission Physiol Rev, January 1, 2009; 89(1): 309 - 380. [Abstract] [Full Text] [PDF]

				S. Marinelli, S. Pacioni, T. Bisogno, V. Di Marzo, D. A. Prince, J. R. Huguenard, and A. Bacci The Endocannabinoid 2-Arachidonoylglycerol Is Responsible for the Slow Self-Inhibition in Neocortical Interneurons J. Neurosci., December 10, 2008; 28(50): 13532 - 13541. [Abstract] [Full Text] [PDF]

				E. M. Awumey, S. K. Hill, D. I. Diz, and R. D. Bukoski Cytochrome P-450 metabolites of 2-arachidonoylglycerol play a role in Ca2+-induced relaxation of rat mesenteric arteries Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2363 - H2370. [Abstract] [Full Text] [PDF]

				A. Ludanyi, L. Eross, S. Czirjak, J. Vajda, P. Halasz, M. Watanabe, M. Palkovits, Z. Magloczky, T. F. Freund, and I. Katona Downregulation of the CB1 Cannabinoid Receptor and Related Molecular Elements of the Endocannabinoid System in Epileptic Human Hippocampus J. Neurosci., March 19, 2008; 28(12): 2976 - 2990. [Abstract] [Full Text] [PDF]