Endocannabinoid overload.
The signaling capacity of endogenous cannabinoids ("endocannabinoids") is tightly regulated by degradative enzymes. This Perspective highlights a research article in this issue (p. 996) in which the authors show that genetic disruption of monoacylglycerol lipase (MAGL), the principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), causes marked elevations in 2-AG levels that lead to desensitization of brain cannabinoid receptors. These findings highlight the central role that MAGL plays in endocannabinoid metabolism in vivo and reveal that excessive 2-AG signaling can lead to functional antagonism of the brain cannabinoid system.
The Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA 23298, USA. alichtma@vcu.edu
Aron H
AH
Lichtman
Jacqueline L
JL
Blankman
Benjamin F
BF
Cravatt
D000818:Animals; D001095:Arachidonic Acids / Q000502:physiology; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D015536:Down-Regulation / Q000502:physiology; D063388:Endocannabinoids; D005989:Glycerides / Q000502:physiology; D006801:Humans; D008994:Monoacylglycerol Lipases / Q000502:physiology; D043882:Receptors, Cannabinoid / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D043882:Receptors, Cannabinoid; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases