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Science Signaling  10 Jan 2012:
Vol. 5, Issue 206, pp. ec10
DOI: 10.1126/scisignal.2002828

Binding of the endocannabinoid anandamide to the cannabinoid CB1 receptor can trigger analgesia and attenuate inflammation. Termination of anandamide signaling is thought to involve removal of anandamide from the synaptic space through a transporter or transporters, followed by hydrolysis of anandamide in cells by the membrane-bound amidases FAAH-1 (fatty acid amide hydrolase 1) and FAAH-2 (see Marsicano and Chaouloff). Pharmacological inhibition of either the transport or catabolism of anandamide enhances CB1-dependent processes. By characterizing a splice variant of the Faah gene, Fu et al. identified a transporter that mediates the cellular uptake of anandamide. This splice variant, which the authors named FLAT (FAAH-like anandamide transporter), lacked amino acid residues 9-76 of FAAH-1 and was predicted by structural modeling to be more water-soluble than FAAH-1. Like FAAH-1, FLAT bound to anandamide; however, FLAT did not show amidase activity toward anandamide in transfected HEK cells. The accumulation of radioactive anandamide was increased in HEK cells transfected with FLAT compared to that in vector-transfected cells and was blocked by incubating cells with inhibitors of anandamide transport or with nonradioactive anandamide. Small-molecule screening for a FLAT inhibitor identified ARN272, which competitively antagonized the binding of radioactive anandamide to FLAT in vitro and inhibited anandamide accumulation in FLAT-expressing HEK cells and cortical neuron cultures. Mice treated with ARN272 had a higher plasma concentration of anandamide, and ARN272 reduced the pain and inflammation caused by injection of two different compounds (formalin and carrageenan). Thus, the cellular uptake of anandamide is mediated by a catalytically inactive form of an enzyme that catabolizes anandamide.

J. Fu, G. Bottegoni, O. Sasso, R. Bertorelli, W. Rocchia, M. Masetti, A. Guijarro, A. Lodola, A. Armirotti, G. Garau, T. Bandiera, A. Reggiani, M. Mor, A. Cavalli, D. Piomelli, A catalytically silent FAAH-1 variant drives anandamide transport in neurons. Nat. Neurosci. 15, 64–69 (2012). [PubMed]

G. Marsicano, F. Chaouloff, Moving bliss: A new anandamide transporter. Nat. Neurosci. 15, 5–6 (2012). [PubMed]

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