Schematic of Anandamide Uptake and Inactivation. Endogenous anandamide (AEA) passes through the cellular membrane without the need for a protein transporter and is shuttled through the aqueous environment of the cytoplasm with the fatty acid binding protein transporters (FABPs) to endoplasmic reticulum (ER) localized fatty acid amide hydrolase (FAAH) for catabolism. FAAH drives the uptake and inhibition of FAAH or the FABPs reduces the rate of anandamide breakdown and raises the AEA levels for signaling at the receptor (taken from A Personal Retrospective: Elevating Anandamide (AEA) by Targeting Fatty Acid Amide Hydrolase (FAAH) and the Fatty Acid Binding Proteins (FABPs). Deutsch DG. Front Pharmacol. 2016 Oct 13;7:370).
Nearly all neurotransmitters are water soluble and, as such, require a transmembrane protein transporter to pass through the lipid membrane for inactivation inside the cell. However, using model systems, we and others have shown that this is unnecessary for anandamide, an uncharged hydrophobic molecule that readily diffuses across the cellular membrane. Interestingly, its uptake is driven by the concentration gradient resulting from its breakdown mainly by FAAH localized in the endoplasmic reticulum.
We identified the FABPs as intracellular carriers that “solubilize” anandamide, transporting anandamide to FAAH. As shown in the Figure, inhibiting the FABPs will reduce the AEA delivery to FAAH and disrupt the outward/inward concentration gradient driven by FAAH. Compounds that bind to FABPs block AEA breakdown, raising its level. Targeting FABPs may be advantageous since they have some tissue specificity and do not require reactive serine hydrolase inhibitors, as does FAAH, with potential for off-target reactions. Specific inhibitors of the FABPs were developed at Stony Brook such as SBFI26 that led to an increase in AEA levels in the periphery and brains of animals and they had analgesic effects.
The cannabinoids (THC and CBD) also were discovered to bind FABPs and this may be one of the mechanisms by which CBD works in childhood epilepsy, raising anandamide levels. We are continuing our drug discovery program, with five collaborators, to make better FABP inhibitors and we also looking at the FABP transport of cannabinoids in liver for metabolism at the cytochrome P450s.