title: The ligand specificity of the G-protein-coupled receptor GPR34.
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 compounds. The results of the present study suggest that lyso-PS has only a random agonistic activity at some GPR34 orthologues and the search for the endogenous agonist should consider additional chemical entities.
authors.affiliation: Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Ritscher
authors.forename: Eva
authors.initials: E
authors.lastname: Engemaier
authors.forename: Claudia
authors.initials: C
authors.lastname: Stäubert
authors.forename: Ines
authors.initials: I
authors.lastname: Liebscher
authors.forename: Philipp
authors.initials: P
authors.lastname: Schmidt
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermsdorf
authors.forename: Holger
authors.initials: H
authors.lastname: Römpler
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D008024:Ligands; D016013:Likelihood Functions; D049312:Receptors, Lysophospholipid / Q000378:metabolism*
chemical_list: C118065:G-protein-coupled receptor 34; D008024:Ligands; D049312:Receptors, Lysophospholipid