The active component of marijuana is D-9-tetrahydrocannabinol (THC), which binds to two different receptors – the CB1 receptor, which mediates the psychotropic effects of marijuana, and the CB2 receptor, which mediates anti-inflammatory effects. These receptors did not evolve to bind a plant natural product – rather THC mimics endogenous activators of the cannabinoid receptors. These endogenous activators are called endocannabinoids and the two primary endocannabinoids are the arachidonic acid derivatives, 2-arachidonoylglycerol (2-AG) and arachidonylethanolamide (AEA).
Our laboratory recently discovered that 2-AG and AEA are selective substrates for COX-2 and we are investigating the physiological implications of this discovery. We have found that 2-AG and AEA are oxygenated to prostaglandin glyceryl esters and prostaglandin ethanolamides, respectively. We have characterized the pathways by which 2-AG is released in response to cell stimulation and we have shown that this transformation occurs in intact cells treated with physiological agonists. We have also found that certain prostaglandin glyceryl esters exert biological effects that appear to be mediated by unique and specific receptors. We are attempting to identify these receptors and to evaluate the physiological roles of this novel class of lipid mediators. Our discoveries provide a linkage between the catalytic action of COX-2 and endogenous cannabinoid signaling.
C.A. Rouzer and L.J. Marnett “Non-Redundant Functions of Cyclooxygenases: Oxygenation of Endocannabinoids,” J.Biol.Chem., 283, 8065-8069 (2008)
M.V. Turman, P.J. Kingsley, C.A. Rouzer, B.F. Cravatt, and L.J. Marnett “Oxidative Metabolism of a Fatty Acid Amide Hydrolase-Regulated Lipid, Arachidonoyltaurine,” Biochemistry, 47, 3917-3925 (2008)
C.A. Rouzer, P.T. Ivanova, M.O. Byrne, H.A. Brown, and L.J. Marnett “Lipid Profiling Reveals Glycerophospholipid Remodeling in Zymosan-Stimulated Macrophages,” Biochemistry, 22, 6026-6042 (2007)