Prostaglandin E₂ glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y₆.

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 E₂, PGE₂-G, mobilizes Ca²⁺ and activates protein kinase C and ERK, suggesting the involvement of a G protein-coupled receptor (GPCR). To identify the endogenous receptor for PGE₂-G, we performed a subtractive screening approach where mRNA from PGE₂-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 PGE₂-G responder cell lines. Using a set of functional readouts in heterologous and endogenous expression systems, we identified the UDP receptor P2Y₆ as the specific target of PGE₂-G. We show that PGE₂-G and UDP are both agonists at P2Y₆, but they activate the receptor with extremely different EC₅₀ values of ~1 pM and ~50 nM, respectively. The identification of the PGE₂-G/P2Y₆ pair uncovers the signalling mode of PG-Gs as previously under-appreciated products of cyclooxygenase-2.

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