Inactivation and Biotransformation of the Endogenous Cannabinoids Anandamide and 2-Arachidonoylglycerol

Abstract

The cannabinoid field is currently an active research area.

Evidence for Bidirectional Endocannabinoid Transport across Cell Membranes

“…There are both in vitro (12,63) and in vivo (67-70) data supporting the existence of a putative anandamide EMT. However, other EMT-independent AEA uptake mechanisms have been proposed, such as caveolae-related endocytosis (27,71) and FAAH-driven facilitated diffusion (24,25,72). More recently, different cytoplasmic AEA-binding proteins (FABPs, Hsp70, albumin, and FLAT) and intracellular compartments (adiposomes) have been shown to be important for the cellular uptake of AEA (9,11,60,73).…”

Stimulatory and Inhibitory Roles of Brain 2-Arachidonoylglycerol in Bombesin-Induced Central Activation of Adrenomedullary Outflow in Rats

“…In the nervous system, 2-AG produced on demand from membrane phospholipids of postsynaptic neurons acts on presynaptic cannabinoid CB 1 receptors, thereby inhibiting the release of neurotransmitters (21,22). The 2-AG released into the synaptic cleft seems to be rapidly inactivated by uptake into neurons (23). This 2-AGinduced retrograde signaling process seems to be involved in widespread effects, including synaptic plasticity (24), analgesia (25), neuroprotection and neurotoxicity (26,27), food intake (24,28), and also in the baroreflexevoked central sympathetic modulation (29).…”

Endocannabinoid Transport Revisited

“…Yet, FAAH cannot be fully responsible for AEA uptake and additional proteins involved in AEA transport across the plasma membrane were proposed . Cell type-dependent differences in which AEA uptake and FAAH-mediated hydrolysis are more or less tightly coupled were described (Yates & Barker, 2009a, 2009b. In agreement with the view that FAAH is not the only player in AEA transport, cells lacking FAAH such as like HMC-1 cells Maccarrone, Fiorucci, et al, 2000;Nicolussi, Chicca, et al, 2014;Nicolussi, Viveros-Paredes, et al, 2014) show robust AEA uptake kinetics, although with a lower V max than in FAAH-expressing cells.…”

“…As a note, at !1 μM AEA simple diffusion kinetics can be readily measured, yet such high concentrations are not found in tissues. Thus, the explanation that the dissimilar results were due to cell type-specific mechanisms or experimental variability within the assays (Yates & Barker, 2009a, 2009b) could be complemented with the different AEA concentrations used. The model of simple AEA diffusion across the cell membrane has in fact been repetitively challenged by numerous biochemical studies probing AEA cellular uptake with the existing older and newer inhibitors (Table 1).…”

“…One reason for this is that transport assay conditions for 2-AG uptake are greatly hampered by the fact that 2-AG is degraded rapidly by both intracellular and extracellular hydrolases, which are differentially expressed in different cell types (vide infra). To date, several hypothetical models have been proposed and reviewed for AEA uptake (Felder, Dickason-Chesterfield, & Moore, 2006;Yates & Barker, 2009a, 2009b. Due to the difficulty of transport assay handling, differential transport kinetics as a function of concentration, the lack of an identified endocannabinoid membrane transporter (EMT), and the biases of researchers, there is an ongoing thought-provoking debate on the transport mechanism of endocannabinoids across the plasma membrane (Fowler, 2012(Fowler, , 2013Yates & Barker, 2009a, 2009b.…”