Role for the Guanine Nucleotide Exchange Factor Phosphatidylinositol-3,4,5-Trisphosphate–Dependent Rac Exchanger 1 in Platelet Secretion and Aggregation
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, JNK, 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 and its role in platelet secretion, as well as aggregation induced by low-dose agonists for GPCR and by collagen.
- Received July 17, 2011.
- Accepted December 8, 2011.
- © 2011 American Heart Association, Inc.