Abstract
The endocannabinoid system modulates numerous physiological processes including nociception and reproduction. Anandamide (AEA) is an endocannabinoid that is inactivated by cellular uptake followed by intracellular hydrolysis by fatty acid amide hydrolase (FAAH). Recently, FAAH-like anandamide transporter (FLAT), a truncated and catalytically-inactive variant of FAAH, was proposed to function as an intracellular AEA carrier and mediate its delivery to FAAH for hydrolysis. Pharmacological inhibition of FLAT potentiated AEA signaling and produced antinociceptive effects. Given that endocannabinoids produce analgesia through central and peripheral mechanisms, the goal of the current work was to examine the expression of FLAT in the central and peripheral nervous systems. In contrast to the original report characterizing FLAT, expression of FLAT was not observed in any of the tissues examined. To investigate the role of FLAT as a putative AEA binding protein, FLAT was generated from FAAH using polymerase chain reaction and further analyzed. Despite its low cellular expression, FLAT displayed residual catalytic activity that was sensitive to FAAH inhibitors and abolished following mutation of its catalytic serine. Overexpression of FLAT potentiated AEA cellular uptake and this appeared to be dependent upon its catalytic activity. Immunofluorescence revealed that FLAT localizes primarily to intracellular membranes and does not contact the plasma membrane, suggesting that its capability to potentiate AEA uptake may stem from its enzymatic rather than transport activity. Collectively, our data demonstrate that FLAT does not serve as a global intracellular AEA carrier, although a role in mediating localized AEA inactivation in mammalian tissues cannot be ruled out.
Highlights
The endocannabinoid anandamide (AEA) is an endogenous ligand for cannabinoid receptors [1]
Because previous reports have shown that the antinociceptive effects of endocannabinoids may be mediated by peripheral cannabinoid receptors [11], we sought to ascertain whether FAAH-like anandamide transporter (FLAT) is expressed in peripheral nerves and whether its antinociceptive effects are mediated through a peripheral endocannabinoid mechanism
We examined the expression of FLAT in mouse brain, spinal cord, and L3-L5 dorsal root ganglia (DRG)
Summary
The endocannabinoid anandamide (AEA) is an endogenous ligand for cannabinoid receptors [1]. Through activation of cannabinoid receptors, AEA regulates a plethora of biological processes including nociception, inflammation, reproduction, and gastric motility [2,3,4]. AEA signaling is terminated through catabolism by the endoplasmic reticulum-localized enzyme fatty acid amide hydrolase (FAAH) [5,6,7]. Prior to reaching FAAH, lipophilic AEA requires transport through the aqueous cytosol. Several intracellular AEA binding proteins have been identified including fatty acid binding proteins (FABPs), Hsp, and most recently FAAH-like anandamide transporter (FLAT) [8,9,10]. Because previous reports have shown that the antinociceptive effects of endocannabinoids may be mediated by peripheral cannabinoid receptors [11], we sought to ascertain whether FLAT is expressed in peripheral nerves and whether its antinociceptive effects are mediated through a peripheral endocannabinoid mechanism
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