A catalytically silent FAAH-1 variant drives anandamide transport in neurons
Open accessAbstract
The endocannabinoid anandamide is removed from the synaptic space by a selective transport system, expressed in neurons and astrocytes, that remains molecularly uncharacterized. Here we describe a partly cytosolic variant of the intracellular anandamide-degrading enzyme fatty acid amide hydrolase-1 (FAAH-1), termed FAAH-like anandamide transporter (FLAT), that lacked amidase activity but bound anandamide with low micromolar affinity and facilitated its translocation into cells. Known anandamide transport inhibitors, such as AM404 and OMDM-1, blocked these effects. We also identified a competitive antagonist of the interaction of anandamide with FLAT, the phthalazine derivative ARN272, that prevented anandamide internalization in vitro, interrupted anandamide deactivation in vivo and exerted profound analgesic effects in rodent models of nociceptive and inflammatory pain, which were mediated by CB(1) cannabinoid receptors. The results identify FLAT as a critical molecular component of anandamide transport in neural cells and a potential target for therapeutic drugs.
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- Authors
- Fu, J., Bottegoni, G., Sasso, O., Bertorelli, R., Rocchia, W., Masetti, M., Guijarro, A., Lodola, A., Armirotti, A., Garau, G., Bandiera, T., Reggiani, A., Mor, M., Cavalli, A., & Piomelli, D.
- Affiliations
- University of California, Irvine (US)
- Italian Institute of Technology (IT)
- University of Parma (IT)
- Corresponding author
- Piomelli, Daniele
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2011-11-20
- Volume
- 15
- Issue
- 1
- Pages
- 64-69
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC3245783
- OpenAlex
- W2008818829
- Cited by
- 175
- References
- 50
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 15 · 2016: 15 · 2015: 16 · 2014: 31 · 2013: 29 · 2012: 25
- FWCI
- 21.09
- Type
- journal article
- Language
- en
- Update notices
- erratum (2013-11-22)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- Funders
- University of California, Irvine
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Drug Abuse (DA012413, R01DA012413)
- National Institute of General Medical Sciences (R01GM093937)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- flats, fatty acid amide hydrolase, alternative splicing, synaptic cleft, neurons, astrocytes, AM404, CB1 receptor, analgesia, inflammatory pain, nociceptive pain, cannabinoid therapeutics
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Arachidonic Acids, Benzyl Compounds, Neurons, Protein Transport, Rats, Polyunsaturated Alkamides, Endocannabinoids
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