Fig. 1.

Complexity, redundancy, and promiscuity of the endocannabinoid system: the “endocannabinodome” and the interactions therewith of plant cannabinoids. Several often concurrent pathways underlie both the biosynthesis and the inactivation of the 2 most studied endocannabinoids, anandamide, and 2-arachidonoylglycerol (2-AG). Anandamide biosynthetic precursors, the N-arachidonoyl-phosphatidylethanolamines, are produced from the remodeling of phospholipids via the action of N-acyl-transferases (NATs). They are then converted to anandamide, either in 1 step, by N-acyl-phosphatidylethanolamine-selective phospholipase D (NAPE-PLD), or in sequential steps, i.e. by α,β -hydrolase-4 (ABHD4) followed by phosphodiesterase GDE1; or soluble phospholipase A2 (sPLA2) followed by lysophospholipase D (lyso-PLD); or by phospholipase C (PLC) enzymes followed by phosphatases such as PTPN22. The sn-2-arachidonate-containing diacylglycerols serving as biosynthetic precursors for 2-AG are in most cases produced from the action of PLCβ but can also come from phosphatidic acid (PA) via PA phosphohydrolase. However, 2-AG can be also produced from sn-1-lyso-phospholipids via the sequential action of phospholipase A1 (PLA1) and lyso-phospholipase C, or (not shown here) from the dephosphorylation of lysophosphatidic acid. These biosynthetic pathways are shared by anandamide and 2-AG with other N-acyl-ethanolamines and 2-mono-acyl-glycerols, respectively. These congeners, in most cases, do not activate directly the 2 cannabinoid receptors (denoted as CB₁ and CB₂ here, and as CB₁R and CB₂R in the main text), but have other targets, some of which shown here, such as orphan G-protein-coupled receptors (GPR55, GPR18, GPR119); the transient receptor potential of vanilloid-type 1 (TRPV1) channel; and peroxisome proliferator-activated nuclear receptors (PPARs). However, also anandamide and, to a lesser extent, 2-AG, have been suggested to be capable of activating some of these targets, particularly TRPV1 and GPR55. Anandamide also inhibits the transient receptor potential melastatin type-8 (TRPM8) channel (blue broken arrow). Both anandamide and 2-AG, following their cellular reuptake by cells, which might be facilitated by a yet-to-be-characterized endocannabinoid membrane transporter (EMT), are inactivated inside cells by enzymatic hydrolysis, respectively by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). In some cells FAAH, α,β-hydrolase-6 (ABHD6) and, even less frequently, α,β-hydrolase-12 (ABHD12), can also hydrolyze 2-AG. These enzymes are also responsible for the enzymatic hydrolysys of other N-acyl-ethanolamines and 2-mono-acyl-glycerols, respectively, although N-palmitoyl-ethanolamine is preferentially hydrolyzed by N-acyl-ethanolamine acid amidohydrolase (not shown). The 2 endocannabinoids, but not their non-polyunsaturated congeners, can also be oxidized by cyclooxygenase-2 (COX-2), and then processed by prostaglandin synthases, to produce prostamides, in the case of anandamide, and prostaglandin-glycerol esters, in the case of 2-AG. This latter endocannabinoid, via the action of MAGL or ABHD6, can also act as biosynthetic precursor for the nonphospholipase A2-mediated production of prostanoids. Apart from Δ⁹-tetrahydrocannabinol (THC), plant cannabinoids mentioned in the main text, such as cannabidiol (CBD), CBD acid (CBDA), cannabidivarin (CBDV), cannabigerol (CBG), Δ⁹-tetrahydrocannabivarin (THCV), THCV acid (THCVA), and CBDV acid (CBDVA), either activate (red solid arrows) or inhibit (red broken arrows) some of the receptors and enzymes of the “endocannabinoidome”. However, they often do so at medium–high micromolar concentrations, and the weight of such interactions in their pharmacology, as compared with others that they have also been suggested to exert, has not yet been fully assessed. Abn-CBD = abnormal cannabidiol; DAG = diacylglycerol; PLCβ = phospholipase β. Adapted from Di Marzo [58]