The complications of promiscuity: endocannabinoid action and metabolism

Abstract

In this review, we present our understanding of the action and metabolism of endocannabinoids and related endogenous molecules. It is clear that the interactions between the multiple endocannabinoid-like molecules (ECLs) are highly complex, both at the level of signal transduction and metabolism. Thus, ECLs are a group of ligands active at 7-transmembrane and nuclear receptors, as well as transmitter-gated and ion channels. ECLs and their metabolites can converge on common endpoints (either metabolic or signalling) through contradictory or reinforcing pathways. We highlight the complexity of the endocannabinoid system, based on the promiscuous nature of ECLs and their metabolites, as well as the synthetic modulators of the endocannabinoid system.

Figure 1

Endocannabinoid-like molecules (ECLs). In these structures, R1 is the hydrocarbon side chain, for example, C₁₉H₃₁ (generating arachidonyl/arachidonoyl), C₁₇H₃₃ (generating oleyl/oleoyl) and C₁₅H₃₁ (generating palmityl/palmitoyl). ECLs can be primary amides (a: for example, oleamide, ODA); N-acylethanolamides (b: for example, anandamide, AEA; N-oleoylethanolamide, OEA; N-palmitoylethanolamide, PEA); N-acylamino acids (c: for example, N-arachidonoylglycine, NAGly; N-arachidonoylGABA; N-arachidonoylalanine); N-acyldopamines (d: for example, N-arachidonoyldopamine, NADA; N-oleoyldopamine; N-stearoyldopamine; N-palmitoyldopamine), 2-acylglycerols (e: for example, 2-arachidonoylglycerol, 2AG), 2-alkylglycerols (f: for example, noladin ether-2-arachidonoylglyceryl ether) and O-acylethanolamines (g: for example, virodhamine).

Figure 2

ECL catabolism: a schematic diagram of the enzymatic targets of endocannabinoids in a model cell. The chemical structure is of N-oleoylethanolamine, OEA, which may be hydrolysed at the intracellular face of FAAH1, the extracellular face of FAAH2 or within the lysosome by N-acylethanolamine acid amidase. Also indicated are COX-2 and MAGL, which are capable of metabolizing 2AG and AEA (rather than OEA).

Figure 3

ECL action at receptors: a schematic diagram of the ‘receptor' targets of endocannabinoids in a model cell. The chemical structure is of anandamide, which may act at the intracellular face of the TRPV1 receptor, the extracellular face of 7TM cannabinoid receptors, at undetermined site(s) of the ion channel or connexin gap junctions and at PPARs inside the nucleus.

Figure 4

Compass points or the cannabinoid cartwheel of complicated cross-talk; green lines with arrow tips represent stimulation/enhancement of the indicated activity; red arrows with ball ends represent inhibition; dashed arrows represent unknown or variable relationships; no line represents no effect. For example, it appears that low levels of intracellular calcium enhance TRPV1, while prolonged/excessive calcium exposure leads to TRPV1 desensitization (c). ERK activity appears to have variable enhancing effects on PPAR activity that may be subtype- or tissue-dependent, but appears to have not been studied with respect to the majority of the endocannabinoid system, other than as a target of receptor activation (d). DAGL, diacylglycerol lipase, ERK, extracellular signal-regulated kinase; FAAH, fatty acid amide hydrolase; PKA, protein kinase A; PKC, protein kinase C; MAGL, monoacylglycerol lipase; NAPE-PLD, N-arylphosphatidylethanolamine-phospholipase D; PPAR, peroxisome proliferator-activated receptor.