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Vol. 59, Issue 6, 1369-1375, June 2001
Department of Medicinal Chemistry and Molecular Pharmacology,
Purdue University School of Pharmacy and Pharmacal Sciences,
West Lafayette, Indiana (T.A.D., F.R., E.L.B.); and Department of
Biochemistry and Cell Biology, SUNY Stoney Brook, Stoney Brook, New
York (D.G.D.)
A facilitated transport process that removes the endogenous cannabinoid
anandamide from extracellular spaces has been identified. Once
transported into the cytoplasm, fatty acid amide hydrolase (FAAH) is
responsible for metabolizing the accumulated anandamide. We propose
that FAAH contributes to anandamide uptake by creating and maintaining
an inward concentration gradient for anandamide. To explore the role of
FAAH in anandamide transport, we examined anandamide metabolism and
uptake in RBL-2H3 cells, which natively express FAAH, as well as
wild-type HeLa cells that lack FAAH. RBL-2H3 and FAAH-transfected HeLa
cells demonstrated a robust ability to metabolize anandamide compared
with vector-transfected HeLa cells. This activity was reduced to that
observed in wild-type HeLa cells upon the addition of the FAAH
inhibitor methyl arachidonyl fluorophosphonate. Anandamide uptake was
reduced in a dose-dependent manner by various FAAH inhibitors in both
RBL-2H3 cells and wild-type HeLa cells. Anandamide uptake studies in
wild-type HeLa cells showed that only FAAH inhibitors structurally
similar to anandamide decreased anandamide uptake. Because there is no
detectable FAAH activity in wild-type HeLa cells, these FAAH inhibitors
are probably blocking uptake via actions on a plasma membrane transport
protein. Phenylmethylsulfonyl fluoride, a FAAH inhibitor that is
structurally unrelated to anandamide, inhibited anandamide uptake in
RBL-2H3 cells and FAAH-transfected HeLa cells, but not in wild-type
HeLa cells. Furthermore, expression of FAAH in HeLa cells increased maximal anandamide transport 2-fold compared with wild-type HeLa cells.
These results suggest that FAAH facilitates anandamide uptake but is
not solely required for transport to occur.
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