Protease-activated receptor-3 (PAR3) regulates PAR1 signaling by receptor dimerization

Joseph N. McLaughlin, Myla M. Patterson, Asrar B. Malik

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

Thrombin activates endothelial cell signaling by cleaving the protease-activated receptor-1 (PAR1). However, the function of the apparently nonsignaling receptor PAR3 also expressed in endothelial cells is unknown. We demonstrate here the crucial role of PAR3 in potentiating the responsiveness of PAR1 to thrombin. We tested the hypothesis that PAR1/PAR3 heterodimerization and its effect in modifying G protein selectivity was responsible for PAR3 regulation of PAR1 sensitivity. Using bioluminescent resonance energy transfer-2, we showed that PAR1 had comparable dimerization affinity for PAR3 as for itself. We observed increased Gα13 coupling between the PAR1/3 heterodimer compared with the PAR1/1 homodimer. Moreover, knockdown of PAR3 moderated the PAR1-activated increase in endothelial permeability. These results demonstrate a role of PAR3 in allosterically regulating PAR1 signaling governing increased endothelial permeability. Because PAR3 is a critical determinant of PAR1 function, targeting of PAR3 may mitigate the effects of PAR1 in activating endothelial responses such as vascular inflammation.

Original languageEnglish (US)
Pages (from-to)5662-5667
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number13
DOIs
StatePublished - Mar 27 2007
Externally publishedYes

Keywords

  • Endothelium
  • Functional selectivity
  • G protein
  • Signal transduction
  • Thrombin

ASJC Scopus subject areas

  • General

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