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  • br FAAH regulation of ECB signaling

    2021-09-09


    FAAH regulation of ECB signaling ECBs are fatty JNJ-38877605 synthesis amides and monoacylglyerols functioning as neuromodulator lipids that exhibit rapid (within seconds) on-demand biosynthesis in response to neuronal activation, and are subsequently degraded by specialized catabolic enzymes. There are two known receptors binding ECBs with high affinity – CB1R is the most densely expressed in the brain and is present at high levels in corticolimbic regions mediating anxiety, including the medial prefrontal cortex (mPFC) and hippocampus, as well as the BLA 11, 14, whereas CB2R is mainly found in the periphery but also in some microglia and neuronal populations in the central nervous system (CNS) 15, 16. Unlike most neurotransmitters, however, ECBs are not stored in readily releasable pools, but instead are rapidly synthesized ‘on-demand’ upon depolarization-induced calcium increase. Such biosynthesis occurs tonically and, under strong neuronal activation, phasically. The ECB 2-arachidonoylglycerol (2-AG) is synthesized, postsynaptically, by diacylglycerol lipase, whereas the ECB anandamide (AEA) is predominantly synthesized by N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD), also at postsynaptic sites in regions including the BLA, but also presynaptically at others (e.g., hippocampus) 17, 18. Following their synthesis, ECBs are retrogradely transported into the extracellular space to bind ECB receptors present on presynaptic terminals 19, 20, 21. Stimulation of CB1R recruits various signaling pathways [22]. These pathways include CB1R coupling to Gi/o proteins that reduces adenylyl cyclase activity and downregulates cyclic AMP/protein kinase A signaling [23], by Gβγ-induced phospholipase C-β-mediated increases in intracellular calcium influx, and by activation of mitogen-activated protein kinases 24, 25. In addition, CB1R negatively regulates N- and P/Q-type voltage-gated calcium channels [26] and positively regulates inwardly rectifying K+ channels 26, 27, as well as protein serine/threonine phosphatase 2B (calcineurin, PP2B) to change the phosphorylation state of various effector molecules 28, 29. At this time, the precise contribution of these various signaling pathways to ECB modulation of anxiety remains essentially unknown. Enriching the picture further, the actions of AEA are not restricted to CB1R, given that ECBs also act, sometimes in a non-retrograde manner, at CB2R [30], GPR55 [31], and TRPV1 (transient receptor potential vanilloid type 1) channels 32, 33, 34, as well as other G protein subtypes such as Gs and/or Gq1135, 36. It should be noted that not all of these actions have been demonstrated in the BLA at the present time, and this may become an important consideration for future work given differences in CB1R signaling mechanisms across brain regions [37]. Indeed, recent evidence demonstrates that diverse effects are evident even within the extended amygdala [38], whereas other parts of the amygdala, notably central amygdala subnuclei, remain largely uncharacterized. A key mechanism governing CB1R-mediated signaling is the active degradation of released ECBs. 2-AG is degraded presynaptically by monoacylglycerol lipase (MAGL). By contrast, the catabolic fate of a number of the N-acylethanolamine (NAE) group of ECBs, including N-palmitoyl ethanolamine (PEA) [39], N-oleoyl ethanolamine (OEA), and AEA [40], was suspected to be controlled by a common enzyme as early as 1984 [41]. This enzyme was later identified as the serine hydrolase enzyme, FAAH 42, 43, 44, which was then isolated and cloned and shown to be located postsynaptically [45]. In the rodent brain, the distribution of FAAH overlaps closely with CB1R in many but not all regions. Within amygdala subnuclei, FAAH is highly expressed on pyramidal neurons in the BLA, and to a significantly lesser extent in the central nucleus (CeA) 19, 20, 46, 47. Although activation of CB1R in the BLA causes a decrease in both glutamatergic and GABAergic transmission, there is typically a net reduction in neuronal excitability on application of CB1R agonists, probably due to CB1R-mediated presynaptic inhibition of glutamate release 48, 49. By contrast, CB1R signaling generated by increased AEA can also produce long-term depression of inhibitory transmission in the BLA, a change in synaptic plasticity which can serve to promote excitability 50, 51.