Abstract
Integrin aIIbß3 activation is essential for platelet aggregation and, accordingly, for hemostasis and arterial thrombosis. The aIIbß3 integrin is highly expressed on platelets and requires an activation step for binding to fibrinogen, fibrin or von Willebrand factor (VWF). A current model assumes that the process of integrin activation relies on actomyosin force-dependent molecular changes from a bent-closed and extended-closed to an extended-open conformation. In this paper we review the pathways that point to a functional reversibility of platelet aIIbß3 activation and transient aggregation. Furthermore, we refer to mouse models indicating that genetic defects that lead to reversible platelet aggregation can also cause instable thrombus formation. We discuss the platelet agonists and signaling pathways that lead to a transient binding of ligands to integrin aIIbß3. Our analysis points to the (autocrine) ADP P2Y and P2Y receptor signaling via phosphoinositide 3-kinases and Akt as principal pathways linked to reversible integrin activation. Downstream signaling events by protein kinase C, CalDAG-GEFI and Rap1b have not been linked to transient integrin activation. Insight into the functional reversibility of integrin activation pathways will help to better understand the effects of antiplatelet agents.
Original language | English |
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Article number | 12512 |
Number of pages | 16 |
Journal | International Journal of Molecular Sciences |
Volume | 23 |
Issue number | 20 |
DOIs | |
Publication status | Published - 19 Oct 2022 |
Externally published | Yes |
Keywords
- ADP
- collagen
- fibrinogen
- integrin
- platelets
- thrombin
- Mice
- Animals
- Platelet Glycoprotein GPIIb-IIIa Complex/metabolism
- von Willebrand Factor/metabolism
- Platelet Aggregation Inhibitors/pharmacology therapeutic use metabolism
- Actomyosin/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Platelet Activation
- Platelet Aggregation
- Blood Platelets/metabolism
- Thrombosis/metabolism
- Fibrinogen/metabolism
- Protein Kinase C/metabolism
- Adenosine Diphosphate/metabolism
- Fibrin/metabolism
- Phosphatidylinositols/metabolism