The Hunt for the Putative Epoxyeicosatrienoic Acid Receptor

Epoxyeicosatrienoic acids, or EETs, are signaling molecules formed by the metabolism of arachidonic acid by cytochrome P450 enzymes. They are well-known for their anti-inflammatory effects, their ability to lower blood pressure, and benefits to cardiovascular outcomes. Despite the wealth of data demonstrating their physiological benefits, the putative high-affinity receptor that mediates these effects is yet to be identified. The recent report that the sphingosine-1-phosphate receptor 1 (S1PR1) is a high-affinity receptor for a related epoxy lipid prompted us to ask, "Why has the putative EET receptor not been discovered yet? What information about the discoveries of lipid epoxide receptors can help us identify the putative EET receptor?" In this review, we summarize the evidence supporting that the putative EET receptor exists. We then review the data showing EETs binding to other, low-affinity receptors and the discovery of receptors for similar lipid metabolites that can serve as a model for identifying the putative EET receptor. We hope this review will revitalize the search for this important receptor, which can facilitate the development of anti-inflammatory and cardiovascular therapeutics.