Arachidonic acid directly activates the human DP2 receptor.

Aberrant type 2 inflammatory responses are the underlying cause of the pathophysiology of allergic asthma, allergic rhinitis and other atopic diseases with an alarming prevalence in relevant parts of the western world. A bulk of evidence points out the important role of the DP2 receptor in this inflammation processes. A screening of different polyunsaturated fatty acids (PUFAs) at a fluorescence resonance energy transfer (FRET)-based DP2 receptor conformation sensor expressed in HEK cells revealed an agonistic effect of the prostaglandin (PG) D 2 precursor arachidonic acid (AA) on DP2 receptor activity of about 80% of the effect induced by PGD 2 In a combination of experiments at the conformation sensor and using a BRET-based G protein activation sensor expressed together with DP2 receptor-wt in HEK cells, we found that arachidonic acid act as a direct activator of the DP2 receptor but not DP1 receptor, in a concentration range considered physiologically relevant. Pharmacological inhibition of cyclooxygenases and lipoxygenases as well as cytochrome P450 did not lead to a diminished arachidonic acid response on the DP2 receptor, confirming a direct action of arachidonic acid on the receptor. Significance Statement We identified the prostaglandin precursor arachidonic acid to directly activate the DP2 receptor, a G protein-coupled receptor that is known to play an important role in type 2 inflammation.