Prostaglandin E(2) glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y(6)

Cyclooxygenase-2 catalyses the biosynthesis of prostaglandins from arachidonic acid but also the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 2-arachidonoylglycerol. Previous studies identified PG-Gs as signalling molecules involved in inflammation. Thus, the glyceryl ester of prostaglandin E(2), PGE(2)-G, mobilizes Ca(2+) and activates protein kinase C and ERK, suggesting the involvement of a G protein-coupled receptor (GPCR). To identify the endogenous receptor for PGE(2)-G, we performed a subtractive screening approach where mRNA from PGE(2)-G response-positive and -negative cell lines was subjected to transcriptome-wide RNA sequencing analysis. We found several GPCRs that are only expressed in the PGE(2)-G responder cell lines. Using a set of functional readouts in heterologous and endogenous expression systems, we identified the UDP receptor P2Y(6) as the specific target of PGE(2)-G. We show that PGE(2)-G and UDP are both agonists at P2Y(6), but they activate the receptor with extremely different EC(50) values of ~1 pM and ~50 nM, respectively. The identification of the PGE(2)-G/P2Y(6) pair uncovers the signalling mode of PG-Gs as previously under-appreciated products of cyclooxygenase-2.