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

J Biol Chem. 2009 Jun 19;284(25):17304-17319. doi: 10.1074/jbc.M109.003194. Epub 2009 Apr 14.


Lysophosphatidic acid (LPA) is a ligand for LPA(1-3) of the endothelial differentiation gene family G-protein-coupled receptors, and LPA(4-8) is related to the purinergic family G-protein-coupled receptor. Because the structure-activity relationship (SAR) of GPR92/LPA(5) 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 LPA(5) residues predicted to interact with the headgroup of LPA. Four residues involved in ligand recognition in LPA(5) 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 LPA(5) 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 LPA(5) 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 LPA(5) agonists. A pharmacophore model of LPA(5) binding requirements was developed for in silico screening, which identified two non-lipid LPA(5) antagonists. Because LPA(5) transcripts are abundant in human platelets, we tested its antagonists on platelet activation and found that these non-lipid LPA(5) antagonists inhibit platelet activation. The present results suggest that selective inhibition of LPA(5) may provide a basis for future anti-thrombotic therapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites / genetics
  • Calcium Signaling
  • Humans
  • In Vitro Techniques
  • Ligands
  • Lysophospholipids / chemistry
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Platelet Activation / drug effects
  • Platelet Activation / physiology*
  • Receptors, Lysophosphatidic Acid / agonists
  • Receptors, Lysophosphatidic Acid / antagonists & inhibitors
  • Receptors, Lysophosphatidic Acid / chemistry
  • Receptors, Lysophosphatidic Acid / genetics
  • Receptors, Lysophosphatidic Acid / physiology*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship


  • LPAR5 protein, human
  • Ligands
  • Lysophospholipids
  • Receptors, Lysophosphatidic Acid
  • Recombinant Proteins