Endogenous cannabinoids (endocannabinoids) are an important class of signaling lipids that act on both central and peripheral cannabinoid receptors, which also mediate the effects of delta9-tetrahydrocannabinol, the active component of marijuana.    The magnitude and duration of endocannabinoid signaling are tightly controlled in vivo by the action of multiple biosynthetic and degradative enzymes.  Here, I will discuss our lab's efforts to develop selective genetic and pharmacological tools to perturb the function of individual endocannabinoid metabolic enzymes. These tools have not only confirmed key roles for enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), in endocannabinoid metabolism, but have also revealed unexpected connectivities between the endocannabinoid system and other lipid signaling pathways, including prostaglandins and lysophospholipids. Such 'systems-level' interactions designate endocannabinoid hydrolases as regulators of larger metabolic networks that may influence diverse physiological and pathological processes, such as cancer, inflammation, and nervous system disorders.

Chemoproteomic approaches for targeting endocannabinoid signaling networks

245th National Meeting (2013)

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