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.
