1.4.1 The complexity of the endocannabinoid system - the “endocannabinoidome”
With the advancement of studies, ES has proven to be increasingly complex, since in addition to endocannabinoids of a lipophilic nature, with AEA and 2-AG acting as ligands for CB1 and CB2 receptors, it maintains a relationship with several other mediators such as N- acylethanolamines and 2-acylglycerols, primary amides, lipoamino acids and N-acyl neurotransmitters, with SE-specific enzymes and metabolic enzymes such as fatty acid amide hydrolase (FAAH), N-acyl-phosphatidyl ethanolamine-specific phospholipase (NAPE-PLD), monoacylglycerol lipase (MAGL), DAGL (sn-1-diacylglycerol lipase) and diacylglycerol lipase β (DAGLβ) and other receptors such as peroxisome proliferator-actived receptor α (PPARα), G protein-coupled receptor 118 (GPR118), G protein-coupled receptor 119 (GPR119), GPR55, TRPV1, PPARγ, T-type Ca2+ channels (Cav3.2), TRPM8, 5-HT1A and GABAA. In this sense, the therapeutic targeting of anabolic or catabolic endocannabinoid enzymes has been hampered by the promiscuity of this system, which interacts with several neuromediators, such as endogenous opioids and GABA, forming a broad alternative network of metabolic pathways and processes [10, 35-37]. Therefore, just as the terms transcriptome, proteome and metabolome emerged, the term “endocannabinoidome” has been used [36, 38-41].
It must be considered that alternative synthesis routes, both for AEA and for 2-AG, have been reported. In the case of AEA, those cited as alternative pathways to ”transacylation-phosphodiesterase” are FLC-like/protein tyrosine phosphatase N22 (PTPN22) [42-44], phospholipase A2/lyso-FLD [43, 45] and alpha-beta hydrolase-4/glycerophosphodiesterase GDE1 (Abh4/GDE1) [46]. Furthermore, anandamide can interact with several molecular targets, including the activation of postsynaptic TRPV1 channels at an intracellular site [47]. Such activation may inhibit diacylglycerol lipase α (DAGLα), resulting in a decrease in 2-AG production, thus constituting a regulatory feedback mechanism [43].
Regarding the synthesis of 2-AG, according to Kano et al. [48] other pathways have been proposed including sequential reactions by phospholipase A1 (PLA1) and lysoPI-specific PLC, the conversion of 2-arachidonoyl lysophosphatidic acid into 2 -AG by phosphatase, and the formation of 2-arachidonoyl phosphatidic acid by 1-acyl-2-arachidonoylglycerol.
Both AEA and 2-AG were able to interact with other targets such as GPR55 [43]. As well as reactions involving the arachidonate cascade enzymes, cyclooxygenase-2 (COX-2), originating prostaglandins-ethanolamides (prostamides) and lipoxygenase-12 and -15 (LOX-12-15), also including cytochrome p450 oxygenase enzymes have been mentioned by some authors as exhibiting a catabolic potential for both endocannabinoids [43, 48, 49].
In this context, we briefly illustrate in fig. 1 the complexity of the ES.
Fig. 1. The complexity of the ES