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Adenosine diphosphate (ADP)-induced thromboxane A(2) generation in human platelets requires coordinated signaling through integrin alpha(IIb)beta(3) and ADP receptors
- Source :
- Blood. 99(1)
- Publication Year :
- 2002
-
Abstract
- Adenosine diphosphate (ADP) is a platelet agonist that causes platelet shape change and aggregation as well as generation of thromboxane A(2), another platelet agonist, through its effects on P2Y1, P2Y12, and P2X1 receptors. It is now reported that both 2-propylthio-D-beta gamma-dichloromethylene adenosine 5'-triphosphate (AR-C67085), a P2Y12 receptor-selective antagonist, and adenosine-2'-phosphate-5'-phosphate (A2P5P), a P2Y1 receptor-selective antagonist, inhibited ADP-induced thromboxane A(2) generation in a concentration-dependent manner, indicating that coactivation of the P2Y12 and P2Y1 receptors is essential for this event. SC49992, a fibrinogen receptor antagonist, blocked ADP-induced platelet aggregation and thromboxane A(2) production in a concentration-dependent manner. Similarly, P2 receptor antagonists or SC49992 blocked ADP-induced arachidonic acid liberation. Whereas SC49992 blocked arachidonic acid-induced platelet aggregation, it failed to inhibit thromboxane A(2) generation induced by arachidonic acid. Thus, ADP-induced arachidonic acid liberation, but not subsequent conversion to thromboxane A(2), requires outside-in signaling through the fibrinogen receptor. The Fab fragment of ligand-induced binding site-6 (LIBS6) antibody, which induces a fibrinogen-binding site on the integrin alpha(IIb)beta(3), caused both platelet aggregation and thromboxane A(2) generation. Inhibitors of phosphoinositide 3-kinase, Syk, Src kinases, or protein tyrosine phosphatases inhibited platelet aggregation but not thromboxane A(2) generation, indicating that these signaling molecules have no significant role in phospholipase A(2) activation. In the presence of P2 receptor antagonists A2P5P or AR-C67085, LIBS6 failed to generate thromboxane A(2), suggesting that inside-out signaling through ADP receptors is necessary for this event. It was concluded that both outside-in signaling from the fibrinogen receptor and inside-out signaling from the P2Y1 and P2Y12 receptors are necessary for phospholipase A(2) activation, resulting in arachidonic acid liberation and thromboxane A(2) generation.
- Subjects :
- Blood Platelets
medicine.medical_specialty
Platelet Aggregation
Fibrinogen receptor
Thromboxane
Immunology
Platelet Glycoprotein GPIIb-IIIa Complex
Pharmacology
P2 receptor
Biochemistry
Phospholipases A
Thromboxane receptor
Thromboxane A2
chemistry.chemical_compound
Receptors, Purinergic P2Y1
Phospholipase A2
Adenosine Triphosphate
Internal medicine
medicine
Purinergic P2 Receptor Antagonists
Humans
Platelet
Enzyme Inhibitors
biology
Chemistry
Fibrinogen
Membrane Proteins
Cell Biology
Hematology
Dipeptides
Protein-Tyrosine Kinases
Receptors, Purinergic P2Y12
Adenosine Diphosphate
Enzyme Activation
Endocrinology
biology.protein
Thromboxane-A synthase
Protein Tyrosine Phosphatases
Signal Transduction
Subjects
Details
- ISSN :
- 00064971
- Volume :
- 99
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....f53387f821106f64e4585f910a5b32c1