Fatty acid binding proteins (FABPs) are intracellular chaperones that transport lipid cargoes to organelles and nuclear receptors, regulating diverse processes in the brain and peripheral tissues. The mammalian brain expresses three FABPs: FABP3, FABP5, and FABP7, that display distinct regional and cellular distribution patterns and modulate an array of neurological functions. The Arachidonic Acid (AA)-derived endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are FABP ligands and FABP5 exerts a key role in controlling endocannabinoid levels and synaptic signaling. The epoxyeicosatrienoic acids (EETs) are a class of cytochrome P450-catalyzed AA metabolites. The recent findings highlight the possibility that FABPs may broadly regulate the signaling capacity of AA-derived neuroactive lipids, including EETs. Similar to AA, 2-AG and AEA are substrates for cyclooxygenase-2, yielding prostaglandin glyceryl esters and prostamides, respectively. While FABP5 modulates AEA and 2-AG signaling in the brain, it is currently not known whether this function extends to cyclooxygenase metabolites of endocannabinoids. In this study, we characterized the potential interactions between FABPs and various AA-derived lipids including EETs and cyclooxygenase metabolites of endocannabinoids. We identified that brain-expressed FABPs interact with EETs and the peroxisome proliferator-activated receptor gamma agonist 15-deoxy-Δ^12,14-Prostaglandin J2 (15d-PGJ₂). Among these lipids, EETs displayed the highest affinities for FABP3 and FABP5. Further, 15d-PGJ₂ interacted with FABP3 and FABP5, while binding to FABP7 was markedly lower. Molecular modeling identified unique binding interactions of ligands within FABP binding pockets and highlighted the major contributions of steric clashes and acyl chain solvent exposure in dictating FABP affinity and specificity. Thus, we will present in vitro binding analyses, molecular modeling, and ex vivo electrophysiological approaches. Then, will demonstrate that the EETs and 15d-PGJ₂ are novel FABP ligands and also FABPs control EET-mediated synaptic gating.

Sherrye T. Glaser

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