A catalytically silent FAAH-1 variant drives anandamide transport in neurons

Jin Fu, Giovanni Bottegoni, Oscar Sasso, Rosalia Bertorelli, Walter Rocchia, Matteo Masetti, Ana Guijarro, Alessio Lodola, Andrea Armirotti, Gianpiero Garau, Tiziano Bandiera, Angelo Reggiani, Marco Mor, Andrea Cavalli, Daniele Piomelli

Research output: Contribution to journalArticlepeer-review

133 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)64-69
Number of pages6
JournalNature Neuroscience
Volume15
Issue number1
DOIs
Publication statusPublished - 1 Jan 2012
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint

Dive into the research topics of 'A catalytically silent FAAH-1 variant drives anandamide transport in neurons'. Together they form a unique fingerprint.

Cite this