Comparison of anandamide transport in FAAH wild-type and knockout neurons: evidence for contributions by both FAAH and the CB1 receptor to anandamide uptake.

@article{OrtegaGutirrez2004ComparisonOA,
  title={Comparison of anandamide transport in FAAH wild-type and knockout neurons: evidence for contributions by both FAAH and the CB1 receptor to anandamide uptake.},
  author={Silvia Ortega‐Guti{\'e}rrez and Edward G. Hawkins and Alma Viso and Mar{\'i}a L. L{\'o}pez-Rodr{\'i}guez and Benjamin F. Cravatt},
  journal={Biochemistry},
  year={2004},
  volume={43 25},
  pages={
          8184-90
        }
}
The cellular inactivation of the endogenous cannabinoid (endocannabinoid) anandamide (AEA) represents a controversial and intensely investigated subject. This process has been proposed to involve two proteins, a transporter that promotes the cellular uptake of AEA and fatty acid amide hydrolase (FAAH), which hydrolyzes AEA to arachidonic acid. However, whereas the role of FAAH in AEA metabolism is well-characterized, the identity of the putative AEA transporter remains enigmatic. Indeed, the… 

Figures from this paper

Regulation by cannabinoid receptors of anandamide transport across the blood-brain barrier and through other endothelial cells.
The endocannabinoid anandamide (AEA) has many neurovascular activities. However, it is not yet clear how AEA can be metabolized at the neurovascular interface, and how it can move through the
Involvement of Fatty Acid Amide Hydrolase and Fatty Acid Binding Protein 5 in the Uptake of Anandamide by Cell Lines with Different Levels of Fatty Acid Amide Hydrolase Expression: A Pharmacological Study
TLDR
There was a difference in the sensitivities seen in the reduction of uptake for a given degree of FAAH inhibition produced by a reversible FAAH inhibitor, with C6 cells being more sensitive than RBL-2H3 cells, despite rather similar expression levels and activities of FAAh.
A catalytically silent FAAH-1 variant drives anandamide transport in neurons
TLDR
A partly cytosolic variant of the intracellular anandamide-degrading enzyme fatty acid amide hydrolase-1 (FAAH-1), termed FAAH-like an andamide transporter (FLAT), that lacked amidase activity but bound anandamon with low micromolar affinity and facilitated its translocation into cells is described.
Studies of Anandamide Accumulation Inhibitors in Cerebellar Granule Neurons: Comparison to Inhibition of Fatty Acid Amide Hydrolase
TLDR
Comparisons of the potency of five previously described compounds both as inhibitors of AEA and N-palmitoylethanolamine accumulation by cerebellar granule neurons and as inhibitorsof AEA hydrolysis indicate that inhibition of AEE accumulation by neurons is not a result of the inhibition of endocannabinoid hydrolytic activity and is a process different from the accumulation of PEA.
Organized trafficking of anandamide and related lipids.
Inhibition of fatty acid amide hydrolase and monoacylglycerol lipase by the anandamide uptake inhibitor VDM11: evidence that VDM11 acts as an FAAH substrate
TLDR
It is concluded that VDM11 is an inhibitor of FAAH under the assay conditions used here, and that the inhibition may at least in part be a consequence of the compound acting as an alternative substrate.
Anandamide Uptake Is Consistent with Rate-limited Diffusion and Is Regulated by the Degree of Its Hydrolysis by Fatty Acid Amide Hydrolase*
TLDR
The uptake and hydrolysis profiles observed with UCM707, VDM11, OMDM2, and AM1172 mirrored two selective and potent FAAH inhibitors CAY10400 and URB597 (at low concentrations), indicating that weak inhibition of FAAH can have a pronounced effect upon AEA uptake.
Inactivation and Biotransformation of the Endogenous Cannabinoids Anandamide and 2-Arachidonoylglycerol
TLDR
This review serves as an introduction to the endocannabinoid system with an emphasis on the proteins and events responsible for the termination of AEA and 2-AG signaling.
...
...

References

SHOWING 1-10 OF 41 REFERENCES
Role of fatty acid amide hydrolase in the transport of the endogenous cannabinoid anandamide.
TLDR
Examining anandamide metabolism and uptake in RBL-2H3 cells, which natively express FAAH, as well as wild-type HeLa cells that lack FAAH suggest that FAAH facilitates anandamon uptake but is not solely required for transport to occur.
The Cellular Uptake of Anandamide Is Coupled to Its Breakdown by Fatty-acid Amide Hydrolase*
TLDR
The net uptake of anandamide in cultured neuroblastoma (N18) and glioma (C6) cells, which contain FAAH, was decreased by nearly 50% after 6 min of incubation in the presence of MAFP, and inhibition of FAAH increases the levels of extracellularAnandamide, it may be a useful target for the design of therapeutic agents.
Further evidence for the existence of a specific process for the membrane transport of anandamide.
TLDR
It is shown that FAAH alone cannot account for the facilitated diffusion of AEA across the cell membrane, and suggested that at least one protein different from FAAH is required to facilitate AEA transport across the plasma membrane in a selective and bi-directional way.
Evidence against the presence of an anandamide transporter
TLDR
The initial rates (<1 min) of anandamide accumulation in neuroblastoma and astrocytoma cells in culture are investigated and it is determined that uptake is not saturable with increasing concentrations ofAnandamide, suggesting that this process is a process of simple diffusion.
A new perspective on cannabinoid signalling: complimentary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain.
TLDR
The close correspondence in the distribution of FAAH and CB1 in rat brain and the complimentary pattern of CB1 and FAAH expression at the cellular level provides important new evidence that FAAH may participate in cannabinoid signalling mechanisms of the brain.
Uptake and metabolism of [3H]anandamide by rabbit platelets. Lack of transporter?
TLDR
It is reported that rabbit platelets do not possess a carrier-mediated mechanism for the transport of [3H]anandamide into the cell, and the absence of a transporter for anandamide in these cells is suggested.
Structure—Activity Relationships Among N‐Arachidonylethanolamine (Anandamide) Head Group Analogues for the Anandamide Transporter
TLDR
The structural requirements for ligandbinding to the CB1 receptor and binding to the transporter are very different; however, the transporter and FAAH share most, but not all, structural requirements.
Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase
TLDR
Results indicate that FAAH is a key regulator of anandamide signaling in vivo, setting an endogenous cannabinoid tone that modulates pain perception, and may represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.
Accumulation of N‐Arachidonoylethanolamine (Anandamide) into Cerebellar Granule Cells Occurs via Facilitated Diffusion
TLDR
The results suggest that AEA is accumulated by cerebellar granule cells by a protein‐mediated transport process that has the characteristics of facilitated diffusion.
Uptake and metabolism of [3H]anandamide by rabbit platelets
TLDR
It is reported that rabbit platelets do not possess a carrier-mediated mechanism for the transport of [3H]anandamide into the cell, and the absence of a transporter for anandamide in these cells is suggested.
...
...