Role for the guanine nucleotide exchange factor phosphatidylinositol-3,4,5- trisphosphate-dependent rac exchanger 1 in platelet secretion and aggregation

Feng Qian, Guy C. Le Breton, Jia Chen, Jing Deng, John W. Christman, Dianqing Wu, Richard D. Ye*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Objective-Recent studies have shown a role for Rac1 in regulating platelet functions, but how Rac1 is activated in platelets remains unclear. Phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) was originally identified in neutrophils that regulates phagocyte functions. We sought to examine whether P-Rex1 plays a role in platelet activation. Methods and Results-Western blotting showed P-Rex1 expression in mouse and human platelets. Mice lacking P-Rex1 exhibited prolonged bleeding time and increased rebleeding. When challenged with low doses of the G protein-coupled receptor (GPCR) agonists U46619 and thrombin, P-Rex1 -/- platelets displayed significantly reduced secretion and aggregation compared with wild-type platelets. Increasing the concentration of these agonists could overcome the defect. Platelet aggregation induced by collagen, a non-GPCR agonist, was also compromised in the absence of P-Rex1. Along with these phenotypic changes were impaired Rac1 activation; reduced ATP secretion; and decreased phosphorylation of Akt, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase in P-Rex1 -/- platelets on agonist stimulation. Conclusion-These results demonstrate for the first time the presence of P-Rex1 in platelets as well as its role in platelet secretion and aggregation induced by low-dose agonists for GPCR and by collagen.

Original languageEnglish (US)
Pages (from-to)768-777
Number of pages10
JournalArteriosclerosis, thrombosis, and vascular biology
Volume32
Issue number3
DOIs
StatePublished - Mar 2012

Keywords

  • G proteins
  • platelets
  • receptors
  • signal transduction
  • thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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