Journal
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
Volume 457, Issue 5, Pages 1173-1185Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s00424-008-0573-7
Keywords
Ca2+ mobilization; G-protein; IP3; Phospholipase C; Platelets; Rac1
Categories
Ask authors/readers for more resources
Platelet activation at sites of vascular injury is triggered through different signaling pathways leading to activation of phospholipase (PL) C beta or PLC gamma 2. Active PLCs trigger Ca2+ mobilization and entry, which is a prerequisite for adhesion, secretion, and thrombus formation. PLC beta isoenzymes are activated downstream of G protein-coupled receptors (GPCRs), whereas PLC gamma 2 is activated downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors, such as the major platelet collagen receptor glycoprotein (GP) VI or CLEC-2. The mechanisms underlying PLC regulation are not fully understood. An involvement of small GTPases of the Rho family (Rho, Rac, Cdc42) in PLC activation has been proposed but this has not been investigated in platelets. We here show that murine platelets lacking Rac1 display severely impaired GPVI- or CLEC-2-dependent activation and aggregation. This defect was associated with impaired production of inositol 1,4,5-trisphosphate (IP3) and intracellular calcium mobilization suggesting inappropriate activation of PLC gamma 2 despite normal tyrosine phosphorylation of the enzyme. Rac1 (-/-) platelets displayed defective thrombus formation on collagen under flow conditions which could be fully restored by co-infusion of ADP and the TxA(2) analog U46619, indicating that impaired GPVI-, but not G-protein signaling, was responsible for the observed defect. In line with this, Rac1 (-/-) mice were protected in two collagen-dependent arterial thrombosis models. Together, these results demonstrate that Rac1 is essential for ITAM-dependent PLC gamma 2 activation in platelets and that this is critical for thrombus formation in vivo.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available