The ligand specificity of the G-protein-coupled receptor GPR34

The Biochemical Journal
Lars RitscherTorsten Schöneberg

Abstract

Lyso-PS (lyso-phosphatidylserine) has been shown to activate the G(i/o)-protein-coupled receptor GPR34. Since in vitro and in vivo studies provided controversial results in assigning lyso-PS as the endogenous agonist for GPR34, we investigated the evolutionary conservation of agonist specificity in more detail. Except for some fish GPR34 subtypes, lyso-PS has no or very weak agonistic activity at most vertebrate GPR34 orthologues investigated. Using chimaeras we identified single positions in the second extracellular loop and the transmembrane helix 5 of carp subtype 2a that, if transferred to the human orthologue, enabled lyso-PS to activate the human GPR34. Significant improvement of agonist efficacy by changing only a few positions strongly argues against the hypothesis that nature optimized GPR34 as the receptor for lyso-PS. Phylogenetic analysis revealed several positions in some fish GPR34 orthologues which are under positive selection. These structural changes may indicate functional specification of these orthologues which can explain the species- and subtype-specific pharmacology of lyso-PS. Furthermore, we identified aminoethyl-carbamoyl ATP as an antagonist of carp GPR34, indicating ligand promiscuity with non-lipid ...Continue Reading

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Citations

Aug 22, 2014·Glia·Julia PreisslerAngela Schulz
Mar 8, 2014·British Journal of Pharmacology·Yasuyuki KiharaJerold Chun
Jul 11, 2013·Cellular Signalling·Soo-Jin ParkDong-Soon Im
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Jan 10, 2014·Biomolecules & Therapeutics·Dong-Soon Im
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Apr 23, 2014·Biomolecules & Therapeutics·Soo-Jin ParkDong-Soon Im
May 26, 2017·Scientific Reports·Antje BrüserTorsten Schöneberg
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Feb 7, 2016·The Journal of Immunology : Official Journal of the American Association of Immunologists·Elisabeth JägerDiana Le Duc
Dec 23, 2017·British Journal of Haematology·Seongcheol KimPudur Jagadeeswaran

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