Prostaglandin E2 glyceryl ester is an endogenous agonist of the nucleotide receptor P2Y6. 2017

Antje Brüser, and Anne Zimmermann, and Brenda C Crews, and Gregory Sliwoski, and Jens Meiler, and Gabriele M König, and Evi Kostenis, and Vera Lede, and Lawrence J Marnett, and Torsten Schöneberg
Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103, Leipzig, Germany. antje.brueser@medizin.uni-leipzig.de.

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.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000067996 RAW 264.7 Cells A transformed macrophage cell line isolated from ASCITES of mice infected with ABELSON MURINE LEUKEMIA VIRUS. RAW 264.7 Cell Line,264.7 Cell, RAW,264.7 Cells, RAW,Cell, RAW 264.7,Cells, RAW 264.7,RAW 264.7 Cell
D000072756 Protein Conformation, alpha-Helical A secondary structure of proteins that is a right-handed helix or coil, where each amino (N-H) group of the peptide backbone contributes a hydrogen bond to the carbonyl(C alpha-Helical Conformation, Protein,alpha-Helical Protein Conformation,alpha-Helical Structures,alpha-Helices,alpha-Helix,Conformation, Protein alpha-Helical,Conformation, alpha-Helical Protein,Conformations, Protein alpha-Helical,Conformations, alpha-Helical Protein,Protein Conformation, alpha Helical,Protein Conformations, alpha-Helical,alpha Helical Conformation, Protein,alpha Helical Protein Conformation,alpha Helical Structures,alpha Helices,alpha Helix,alpha-Helical Conformations, Protein,alpha-Helical Protein Conformations,alpha-Helical Structure
D000072757 Protein Conformation, beta-Strand A secondary structure of proteins where the amino (N-H) groups of a polypeptide backbone, three to ten amino acids in length, establish hydrogen bonds with the carbonyl (C Protein Conformation, beta-Sheet,beta-Pleated Sheet,beta-Sheet,beta-Sheets,beta-Strand,beta-Stranded Structures,beta-Strands,Conformation, beta-Sheet Protein,Conformation, beta-Strand Protein,Conformations, beta-Sheet Protein,Conformations, beta-Strand Protein,Protein Conformation, beta Sheet,Protein Conformation, beta Strand,Protein Conformations, beta-Sheet,Protein Conformations, beta-Strand,Sheet, beta-Pleated,Sheets, beta-Pleated,beta Pleated Sheet,beta Sheet,beta Sheets,beta Strand,beta Stranded Structures,beta Strands,beta-Pleated Sheets,beta-Sheet Protein Conformation,beta-Sheet Protein Conformations,beta-Strand Protein Conformation,beta-Strand Protein Conformations,beta-Stranded Structure
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013379 Substrate Specificity A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. Specificities, Substrate,Specificity, Substrate,Substrate Specificities

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