Prostaglandin E glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y.

Brüser A, Zimmermann A, Crews BC, Sliwoski G, Meiler J, König GM, Kostenis E, Lede V, Marnett LJ, Schöneberg T
Sci Rep. 2017 7 (1): 2380

PMID: 28539604 · PMCID: PMC5443783 · DOI:10.1038/s41598-017-02414-8

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, PGE-G, mobilizes Ca and activates protein kinase C and ERK, suggesting the involvement of a G protein-coupled receptor (GPCR). To identify the endogenous receptor for PGE-G, we performed a subtractive screening approach where mRNA from PGE-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-G responder cell lines. Using a set of functional readouts in heterologous and endogenous expression systems, we identified the UDP receptor P2Y as the specific target of PGE-G. We show that PGE-G and UDP are both agonists at P2Y, but they activate the receptor with extremely different EC values of ~1 pM and ~50 nM, respectively. The identification of the PGE-G/P2Y pair uncovers the signalling mode of PG-Gs as previously under-appreciated products of cyclooxygenase-2.

MeSH Terms (23)

Animals Binding Sites Cell Line, Tumor Cyclooxygenase 2 Dinoprostone HEK293 Cells High-Throughput Nucleotide Sequencing High-Throughput Screening Assays Humans Kinetics Ligands Mice Molecular Docking Simulation Protein Binding Protein Conformation, alpha-Helical Protein Conformation, beta-Strand Protein Interaction Domains and Motifs Purinergic Agonists RAW 264.7 Cells Receptors, Purinergic P2 Substrate Specificity Thermodynamics Transcriptome

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