Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation

Jesica R. Williams, Anna L. Khandoga, Pankaj Goyal, James I. Fells, Donna H. Perygin, Wolfgang Siess, Abby L. Parrill, Gabor Tigyi, Yuko Fujiwara

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Abstract

Lysophosphatidic acid (LPA) is a ligand for LPA1-3 of the endothelial differentiation gene family G-protein-coupled receptors, and LPA4-8 is related to the purinergic family G-protein-coupled receptor. Because the structure-activity relationship (SAR) of GPR92/LPA5 is limited and whether LPA is its preferred endogenous ligand has been questioned in the literature, in this study we applied a combination of computational and experimental site-directed mutagenesis of LPA5 residues predicted to interact with the headgroup of LPA. Four residues involved in ligand recognition in LPA5 were identified as follows: R2.60N mutant abolished receptor activation, whereas H4.64E, R6.62A, and R7.32A greatly reduced receptor activation. We also investigated the SAR of LPA5 using LPA analogs and other non-lysophospholipid ligands. SAR revealed that the rank order of agonists is alkyl glycerol phosphate > LPA > farnesyl phosphates ≫ N-arachidonoylglycine. These results confirm LPA5 to be a bona fide lysophospholipid receptor. We also evaluated several compounds with previously established selectivity for the endothelial differentiation gene receptors and found several that are LPA5 agonists. A pharmacophore model of LPA5 binding requirements was developed for in silico screening, which identified two non-lipid LPA5 antagonists. Because LPA5 transcripts are abundant in human platelets, we tested its antagonists on platelet activation and found that these non-lipid LPA5 antagonists inhibit platelet activation. The present results suggest that selective inhibition of LPA5 may provide a basis for future anti-thrombotic therapies.

Original languageEnglish (US)
Pages (from-to)17304-17319
Number of pages16
JournalJournal of Biological Chemistry
Volume284
Issue number25
DOIs
StatePublished - Jun 19 2009

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Platelet Activation
Platelets
Chemical activation
Ligands
Structure-Activity Relationship
G-Protein-Coupled Receptors
Lysophospholipid Receptors
Genes
Phosphates
Mutagenesis
Site-Directed Mutagenesis
Computer Simulation
Glycerol
Screening
Blood Platelets
lysophosphatidic acid

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Williams, J. R., Khandoga, A. L., Goyal, P., Fells, J. I., Perygin, D. H., Siess, W., ... Fujiwara, Y. (2009). Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation. Journal of Biological Chemistry, 284(25), 17304-17319. https://doi.org/10.1074/jbc.M109.003194

Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation. / Williams, Jesica R.; Khandoga, Anna L.; Goyal, Pankaj; Fells, James I.; Perygin, Donna H.; Siess, Wolfgang; Parrill, Abby L.; Tigyi, Gabor; Fujiwara, Yuko.

In: Journal of Biological Chemistry, Vol. 284, No. 25, 19.06.2009, p. 17304-17319.

Research output: Contribution to journalArticle

Williams, JR, Khandoga, AL, Goyal, P, Fells, JI, Perygin, DH, Siess, W, Parrill, AL, Tigyi, G & Fujiwara, Y 2009, 'Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation', Journal of Biological Chemistry, vol. 284, no. 25, pp. 17304-17319. https://doi.org/10.1074/jbc.M109.003194
Williams, Jesica R. ; Khandoga, Anna L. ; Goyal, Pankaj ; Fells, James I. ; Perygin, Donna H. ; Siess, Wolfgang ; Parrill, Abby L. ; Tigyi, Gabor ; Fujiwara, Yuko. / Unique ligand selectivity of the GPR92/LPA5 lysophosphatidate receptor indicates role in human platelet activation. In: Journal of Biological Chemistry. 2009 ; Vol. 284, No. 25. pp. 17304-17319.
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AU - Perygin, Donna H.

AU - Siess, Wolfgang

AU - Parrill, Abby L.

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