Missing Pieces to the Endocannabinoid Puzzle

Cannabis (C. sativa or indica) extracts have emerged as complex mixtures of more than 110 compounds, termed (phyto)cannabinoids. The most active of them is THC, yet it is now apparent that other cannabinoids can also modulate THC effects and/or have their own biological activity. THC activates specific receptors in the human body, known as type-1 (CB1) and type-2 (CB2) cannabinoid receptors, that normally bind eCBs. eCB signaling is complex, as it engages 12 receptors and many biosynthetic and degradative enzymes, as well as transporters and storage organelles. Fine regulation of eCB content and receptor-mediated signaling is crucial, and it appears to occur via canonical and emerging noncanonical mechanisms. THC is able to escape the stringent metabolic control to which the biological activity of eCB is subjected. The most bioactive ingredient of cannabis (Cannabis sativa or indica) extracts, Δ9-tetrahydrocannabinol (THC), was identified in the 1960s as one of more than 110 phytocannabinoids. It activates receptors of chemically different endogenous ligands (endocannabinoids) that, unlike THC, are metabolized by several enzymes of the endocannabinoid system. Here, the complexity of the plant-derived and endogenous cannabinoids (eCBs) is discussed, to better appreciate the challenge of: (i) dissecting their mutual interactions; (ii) understanding their impact on human pathophysiology; and (iii) exploiting them for human disease. To this aim, missing pieces to the eCB puzzle must be urgently found, by solving the 3D structures of key components, and interrogating noncanonical modes of regulation and trafficking of these lipid signals. The most bioactive ingredient of cannabis (Cannabis sativa or indica) extracts, Δ9-tetrahydrocannabinol (THC), was identified in the 1960s as one of more than 110 phytocannabinoids. It activates receptors of chemically different endogenous ligands (endocannabinoids) that, unlike THC, are metabolized by several enzymes of the endocannabinoid system. Here, the complexity of the plant-derived and endogenous cannabinoids (eCBs) is discussed, to better appreciate the challenge of: (i) dissecting their mutual interactions; (ii) understanding their impact on human pathophysiology; and (iii) exploiting them for human disease. To this aim, missing pieces to the eCB puzzle must be urgently found, by solving the 3D structures of key components, and interrogating noncanonical modes of regulation and trafficking of these lipid signals. a compound that modulates enzyme or receptor activity by binding at an allosteric site other than the active site. Such allosteric binding causes a conformational change in the protein, that can be either positive (increased activity, due to PAMs) or negative (reduced activity, due to NAMs). N-arachidonoylethanolamine, that is the amide of arachidonic acid [5,8,11,14-eicosatetraenoic acid, an essential (diet-derived) fatty acid] with ethanolamine, named after the Sanskrit word ‘ananda’ for inner bliss. due to biased ligands that are able to selectively trigger some signaling pathways, while avoiding (or even inactivating) others that are dependent on the same receptor. G protein-coupled receptors that bind THC, AEA, 2-AG, and other eCBs. Two subtypes are known as CB1 and CB2. officially known as prostaglandin-endoperoxide synthase, is an oxygenase responsible for formation of prostanoids (like thromboxanes, prostaglandins, and prostacyclins) from arachidonic acid. family of guanine nucleotide-binding proteins that act as molecular switches between external stimuli and intracellular signals of a cell. seven-transmembrane domain receptors (also known as serpentine receptors), are a large family of proteins that detect molecules outside the cell, thus activating internal signal transduction pathways and cellular responses via G proteins. Of note, CB1 is the most abundant member of this family in mammalian brain. When these receptors are orphan (i.e., their ligands are unknown), they are usually given the name GPR followed by a number, for example GPR55 and GPR119. enzymes that catalyze similar reactions, but slightly differ from each other in chemical structure, and therefore kinetic properties. a type of ubiquitous nonheme iron enzymes responsible for the oxygenation of arachidonic acid into leukotrienes and lipoxins. superfamily of nuclear receptor transcription factors, that include three members: α, γ, and δ. These PPARs are targets of AEA, 2-AG, and their congeners. according to the International Union of Pure and Applied Chemistry (IUPAC), an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response. a six-transmembrane domain receptor channel that is activated by physical and chemical stimuli, as well as by AEA and 2-AG.