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A Uniform Shear Assay for Human Platelet and Cell Surface Receptors via Cone-plate Viscometry
Published on: June 5, 2019
Glycoprotein Ib-mediated platelet activation. A signalling pathway triggered by thrombin
Frédéric Adam1, Marie-Claude Guillin, Martine Jandrot-Perrus
1INSERM E0348, Faculté Xavier Bichat, Paris, France.
European Journal of Biochemistry
|July 9, 2003
Summary
Platelet glycoprotein GPIb acts as a thrombin receptor, mediating platelet activation, adhesion, and aggregation independently of protease-activated receptors (PARs). This pathway involves secreted ADP and is crucial for hemostasis and thrombosis.
Area of Science:
- Biochemistry
- Hematology
- Cell Biology
Background:
- Thrombin is a key mediator of hemostasis and thrombosis, primarily activating platelets via protease-activated receptors (PARs).
- Platelet glycoprotein Ib (GPIb) is known to bind thrombin and enhance platelet activation at low thrombin concentrations.
- The precise role of GPIb as a direct thrombin receptor, independent of PARs, requires further elucidation.
Purpose of the Study:
- To investigate the potential of platelet glycoprotein GPIb as a direct thrombin receptor.
- To characterize the signaling pathways downstream of thrombin-GPIb interactions.
- To understand the contribution of GPIb-mediated activation to platelet function.
Main Methods:
- Utilized immobilized, proteolytically inactive thrombin to enhance thrombin-GPIb interactions and bypass PAR cleavage.
- Studied platelet activation, including adhesion, spreading, and dense granule secretion, using normal and Bernard Soulier syndrome platelets.
- Employed monoclonal antibodies against GPIb (SZ2) and glycocalicin to inhibit GPIb function.
- Investigated the roles of secreted ADP, cAMP, phosphatidylinositol 3-kinases, and protein kinase C in the signaling pathway.
Main Results:
- Immobilized, inactive thrombin induced platelet adhesion, spreading, and dense granule secretion.
- These effects were dependent on GPIb, as evidenced by deficient responses in Bernard Soulier syndrome platelets and inhibition by anti-GPIb antibodies or glycocalicin.
- Secreted ADP was identified as a critical mediator of GPIb-dependent thrombin activation, modulated by cAMP levels.
- Thrombin-GPIb signaling led to protein tyrosyl phosphorylation, and downstream activation of phosphatidylinositol 3-kinases and protein kinase C was essential for platelet-platelet interactions and phosphorylation.
Conclusions:
- Platelet glycoprotein GPIb functions as a direct thrombin receptor, mediating platelet activation independently of PAR cleavage.
- GPIb-dependent thrombin signaling involves ADP secretion and is regulated by cAMP, leading to protein tyrosine phosphorylation.
- This pathway, involving phosphatidylinositol 3-kinases and protein kinase C, plays a significant role in thrombin-induced platelet aggregation and hemostasis.
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