Enzymatic machinery for endocannabinoid biosynthesis associated with calcium stores in glutamatergic axon terminals
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Endocannabinoids are regarded as retrograde signaling molecules at various types of synapses throughout the CNS. The lipid derivatives anandamide and 2-arachidonoylglycerol (2-AG) are generally thought to be the key molecular players in this process. Previous anatomical and electrophysiological studies provided compelling evidence that the biosynthetic enzyme of 2-AG is indeed localized in the postsynaptic plasma membrane, whereas its target, the CB1 cannabinoid receptor, and the enzyme responsible for its inactivation are both found presynaptically. This molecular architecture of 2-AG signaling is a conserved feature of most synapses and supports the retrograde signaling role of 2-AG. Conversely, the molecular and neuroanatomical organization of synaptic anandamide signaling remains largely unknown. In contrast to its predicted role in retrograde signaling, here we show that N-acylphosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD), a biosynthetic enzyme of anandamide and its related bioactive congeners, the N-acylethanolamines (NAEs), is concentrated presynaptically in several types of hippocampal excitatory axon terminals. Furthermore, high-resolution quantitative immunogold labeling demonstrates that this calcium-sensitive enzyme is localized predominantly on the intracellular membrane cisternae of axonal calcium stores. Finally, the highest density of NAPE-PLD is found in mossy terminals of granule cells, which do not express CB1 receptors. Together, these findings suggest that anandamide and related NAEs are also present at glutamatergic synapses, but the sites of their synthesis and action are remarkably different from 2-AG, indicating distinct physiological roles for given endocannabinoids in the regulation of synaptic neurotransmission and plasticity.
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AEA can be synthesized presynaptically, given the presynaptic presence of the rate-limiting AEA-synthesizing enzyme NAPE-PLD.
“in view of the potential for AEA to be synthesized presynaptically (given the presynaptic presence of the rate-limiting AEA-synthesizing enzyme, NAPE-PLD) (Nyilas et al., 2008)”
From The endocannabinoid system as a target for novel anxiolytic drugs (2017) · cites this paper as Nyilas et al., 2008
2-AG is synthesized postsynaptically by diacylglycerol lipase, whereas AEA is predominantly synthesized by NAPE-PLD, also at postsynaptic sites in regions including the BLA, but also presynaptically at others such as the hippocampus.
“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].”
From Amygdala FAAH and anandamide: mediating protection and recovery from stress (2013) · cites this paper as [17]
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- Authors
- Nyilas, R., Dudok, B., Urbán, G. M., Mackie, K., Watanabe, M., Cravatt, B. F., Freund, T. F., & Katona, I.
- Affiliations
- HUN-REN Institute of Experimental Medicine (HU)
- Hungarian Academy of Sciences (HU)
- Indiana University Bloomington (US)
- Scripps Research Institute (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-01-30
- Volume
- 28
- Issue
- 5
- Pages
- 1058-1063
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6671412
- OpenAlex
- W1970307887
- Cited by
- 119
- References
- 28
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 5 · 2020: 5 · 2019: 1 · 2018: 3 · 2017: 10 · 2016: 2 · 2015: 8 · 2014: 6 · 2013: 5 · 2012: 11
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- European Commission (LSHM‐CT2004‐005166)
- Hungarian Scientific Research Fund (F046407)
- Nemzeti Kutatási és Technológiai Hivatal
- National Institutes of Health
- National Institute on Drug Abuse (DA21696, DA11322, R01DA011322, K05DA021696)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- endocannabinoid biosynthesis, anandamide, NAPE-PLD, N-acylethanolamines, 2-arachidonoylglycerol, retrograde signaling, glutamatergic synapses, mossy fibers, hippocampal granule cells, CB1 receptor, synaptic transmission
- MeSH terms
- Acyltransferases, Animals, Calcium, Male, Mice, Inbred C57BL, Phospholipase D, Synapses, Presynaptic Terminals, Mice, Knockout, Glutamic Acid, Receptor, Cannabinoid, CB1, Mice, Cannabinoid Receptor Modulators, Endocannabinoids
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