Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects
Jonathan Z. Long,Weiwei Li,Lamont Booker,James J. Burston,Steven G. Kinsey,Joel E. Schlosburg,Franciso J Pavón,Antonia Serrano,Dana E. Selley,Loren H. Parsons,Aron H. Lichtman,Benjamin F. Cravatt +11 more
TLDR
2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo, indicating a functional segregation of endocannabinoid signaling pathways in vivo.Abstract:
2-Arachidonoylglycerol (2-AG) and anandamide are endocannabinoids that activate the cannabinoid receptors CB1 and CB2. Endocannabinoid signaling is terminated by enzymatic hydrolysis, a process that for anandamide is mediated by fatty acid amide hydrolase (FAAH), and for 2-AG is thought to involve monoacylglycerol lipase (MAGL). FAAH inhibitors produce a select subset of the behavioral effects observed with CB1 agonists, which suggests a functional segregation of endocannabinoid signaling pathways in vivo. Testing this hypothesis, however, requires specific tools to independently block anandamide and 2-AG metabolism. Here, we report a potent and selective inhibitor of MAGL called JZL184 that, upon administration to mice, raises brain 2-AG by eight-fold without altering anandamide. JZL184-treated mice exhibited a broad array of CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility. These data indicate that 2-AG endogenously modulates several behavioral processes classically associated with the pharmacology of cannabinoids and point to overlapping and unique functions for 2-AG and anandamide in vivo.read more
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BODIPY-based probes for the fluorescence imaging of biomolecules in living cells
TL;DR: Advances in the development of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY)-based fluorescent probes for biological studies over the past decade are covered.
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FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling
Rudolf Zechner,Robert Zimmermann,Thomas O. Eichmann,Sepp D. Kohlwein,Guenter Haemmerle,Achim Lass,Frank Madeo +6 more
TL;DR: New findings that lipolytic products and intermediates participate in cellular signaling processes and that “lipolytic signaling” is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.
Journal ArticleDOI
Monoacylglycerol Lipase Regulates a Fatty Acid Network that Promotes Cancer Pathogenesis
Daniel K. Nomura,Jonathan Z. Long,Sherry Niessen,Heather Hoover,Shu-Wing Ng,Benjamin F. Cravatt +5 more
TL;DR: Overexpression of MAGL in nonaggressive cancer cells recapitulates this fatty acid network and increases their pathogenicity-phenotypes that are reversed by an MAGL inhibitor, indicating that exogenous sources of fatty acids can contribute to malignancy in cancers lacking MAGL activity.
Journal ArticleDOI
Neuroactive Insecticides: Targets, Selectivity, Resistance, and Secondary Effects
TL;DR: Primary toxic effects in mammals from off-target serine hydrolase inhibition include organophosphate-induced delayed neuropathy and disruption of the cannabinoid system.
Journal ArticleDOI
Endocannabinoid Hydrolysis Generates Brain Prostaglandins That Promote Neuroinflammation
Daniel K. Nomura,Daniel K. Nomura,Bradley E. Morrison,Jacqueline L. Blankman,Jonathan Z. Long,Steven G. Kinsey,Maria Cecilia Garibaldi Marcondes,Anna M. Ward,Yun Kyung Hahn,Aron H. Lichtman,Bruno Conti,Benjamin F. Cravatt +11 more
TL;DR: These findings identify MAGL as a distinct metabolic node that couples endocannabinoid to prostaglandin signaling networks in the nervous system and suggest that inhibition of this enzyme may be a new and potentially safer way to suppress the proinflammatory cascades that underlie neurodegenerative disorders.
References
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William A. Devane,Lumir Hanus,Aviva Breuer,Roger G. Pertwee,Lesley A. Stevenson,Graeme Griffin,Dan Gibson,Asher Mandelbaum,A. Etinger,Raphael Mechoulam +9 more
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Raphael Mechoulam,Shimon Ben-Shabat,Lumir Hanus,Moshe Ligumsky,Norbert E. Kaminski,Anthony R. Schatz,Asher Gopher,Shlomo Almog,Billy R. Martin,David R. Compton,Roger G. Pertwee,Graeme Griffin,Michael Bayewitch,Jacob Barg,Zvi Vogel +14 more
TL;DR: Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature.
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2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain
Takayuki Sugiura,Sachiko Kondo,Akihiro Sukagawa,Shinji Nakane,A. Shinoda,K. Itoh,Atsushi Yamashita,Keizo Waku +7 more
TL;DR: 2-Arachidonoylglycerol was shown to bind appreciably to the cannabinoid receptor in competitive inhibition experiments and may be an endogenous cannabinoid receptor ligand in the brain.
Journal ArticleDOI
Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides
Benjamin F. Cravatt,Dan K. Giang,Stephen P. Mayfield,Dale L. Boger,Richard A. Lerner,Norton B. Gilula +5 more
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