Journal
NATURE NEUROSCIENCE
Volume 15, Issue 1, Pages 64-U82Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2986
Keywords
-
Categories
Funding
- US National Institute on Drug Abuse
- US National Institute on Alcohol Abuse and Alcoholism [DA-012413]
- US National Institute on General Medicine [1R01GM093937-01]
- Agilent/University of California Irvine Analytical Discovery Facility
Ask authors/readers for more resources
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 CB1 cannabinoid receptors. The results identify FLAT as a critical molecular component of anandamide transport in neural cells and a potential target for therapeutic drugs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available