PT  - JOURNAL ARTICLE
AU  - Kurz, Michael
AU  - Ulrich, Michaela
AU  - Kirchhofer, Sina B
AU  - Bittner, Alwina
AU  - Daude, Michael
AU  - Diederich, Wibke E
AU  - Pauk, Kim
AU  - Garn, Holger
AU  - Bünemann, Moritz
TI  - Arachidonic acid directly activates the human DP2 receptor
AID  - 10.1124/molpharm.124.000884
DP  - 2024 Jan 01
TA  - Molecular Pharmacology
PG  - MOLPHARM-AR-2024-000884
4099  - http://molpharm.aspetjournals.org/content/early/2024/09/16/molpharm.124.000884.short
4100  - http://molpharm.aspetjournals.org/content/early/2024/09/16/molpharm.124.000884.full
AB  - 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) D2 precursor arachidonic acid (AA) on DP2 receptor activity of about 80% of the effect induced by PGD2. 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.