Lyso-PS (lyso-phosphatidylserine) has been shown to activate the Gi/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.
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Research Article|
April 16 2012
The ligand specificity of the G-protein-coupled receptor GPR34
Lars Ritscher;
Lars Ritscher
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Eva Engemaier;
Eva Engemaier
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Claudia Stäubert;
Claudia Stäubert
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Ines Liebscher;
Ines Liebscher
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Philipp Schmidt;
Philipp Schmidt
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Thomas Hermsdorf;
Thomas Hermsdorf
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Holger Römpler;
Holger Römpler
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Angela Schulz;
Angela Schulz
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
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Torsten Schöneberg
Torsten Schöneberg
1
1Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, Johannisallee 30, 04103 Leipzig, Germany
1To whom correspondence should be addressed (email schoberg@medizin.uni-leipzig.de).
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Publisher: Portland Press Ltd
Received:
November 29 2011
Revision Received:
February 10 2012
Accepted:
February 20 2012
Accepted Manuscript online:
February 20 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (3): 841–850.
Article history
Received:
November 29 2011
Revision Received:
February 10 2012
Accepted:
February 20 2012
Accepted Manuscript online:
February 20 2012
Citation
Lars Ritscher, Eva Engemaier, Claudia Stäubert, Ines Liebscher, Philipp Schmidt, Thomas Hermsdorf, Holger Römpler, Angela Schulz, Torsten Schöneberg; The ligand specificity of the G-protein-coupled receptor GPR34. Biochem J 1 May 2012; 443 (3): 841–850. doi: https://doi.org/10.1042/BJ20112090
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