Structural Biology of Endocannabinoid Targets and Enzymes: Components Tuned to the Flexibility of Endogenous Ligands

The lipid bilayer plays a major role in the “life-cycle” of the endocannabinoids, anandamide and 2-AG. These ligands are synthesized on demand in the lipid bilayer; act at membrane embedded cannabinoid receptors that may be accessed via the lipid bilayer; and, are degraded by membrane associated enzymes that have lipid entry portals for their respective endocannabinoids (2-AG-Monoacylglycerol lipase (MGL); AEA-Fatty acid amide hydrolase (FAAH)). Transport for degradation (especially for AEA) remains a hot research topic, as AEA must leave the plasma membrane and travel inside the cell to FAAH which is associated with the membrane of the endoplasmic reticulum. This review focuses on structural features of each of the components of the endocannabinoid signaling system, including the enodogenous ligands themselves. For the homo-allylic double bond pattern in their arachidonyl acyl chains confers the “dynamic plasticity” that these ligands require to navigate the bilayer, thread through entry portals of the receptors, and enter lipid entry portals of the enzymes that comprise the endocannabinoid signaling system.

Keywords: Cannabinoid, CB1, CB2, GPCR, endocannabinoid, anandamide, 2-AG, FAAH, MGL, FABP, FLAT, EMT, S1P1, lpid entry portal, delta-9- THC, virodhamine, NADA, arachidonic acid, retrograde signaling, GPR18, GPR55.