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Protease-activated receptors 1 and 4 do not stimulate G(i) signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of G(i) signaling
- Source :
- Blood. 99(10)
- Publication Year :
- 2002
-
Abstract
- Thrombin is an important agonist for platelet activation and plays a major role in hemostasis and thrombosis. Thrombin activates platelets mainly through protease-activated receptor 1 (PAR1), PAR4, and glycoprotein Ib. Because adenosine diphosphate and thromboxane A(2) have been shown to cause platelet aggregation by concomitant signaling through G(q) and G(i) pathways, we investigated whether coactivation of G(q) and G(i) signaling pathways is the general mechanism by which PAR1 and PAR4 agonists also activate platelet fibrinogen receptor (alphaIIbbeta3). A PAR1-activating peptide, SFLLRN, and PAR4-activating peptides GYPGKF and AYPGKF, caused inhibition of stimulated adenylyl cyclase in human platelets but not in the presence of either Ro 31-8220, a protein kinase C selective inhibitor that abolishes secretion, or AR-C66096, a P2Y12 receptor-selective antagonist; alpha-thrombin-induced inhibition of adenylyl cyclase was also blocked by Ro 31-8220 or AR-C66096. In platelets from a P2Y12 receptor-defective patient, alpha-thrombin, SFLLRN, and GYPGKF also failed to inhibit adenylyl cyclase. In platelets from mice lacking the P2Y12 receptor, neither alpha-thrombin nor AYPGKF caused inhibition of adenylyl cyclase. Furthermore, AR-C66096 caused a rightward shift of human platelet aggregation induced by the lower concentrations of alpha-thrombin and AYPGKF but had no effect at higher concentrations. Similar results were obtained with platelets from mice deficient in the P2Y12. We conclude that (1) thrombin- and thrombin receptor-activating peptide-induced inhibition of adenylyl cyclase in platelets depends exclusively on secreted adenosine diphosphate that stimulates G(i) signaling pathways and (2) thrombin and thrombin receptor-activating peptides cause platelet aggregation independently of G(i) signaling.
- Subjects :
- Blood Platelets
medicine.medical_specialty
Platelet Aggregation
Immunology
GTP-Binding Protein alpha Subunits, Gi-Go
Biochemistry
Adenylyl cyclase
chemistry.chemical_compound
Thromboxane A2
Mice
P2Y12
Thrombin
Adenosine Triphosphate
Internal medicine
medicine
Purinergic P2 Receptor Antagonists
Animals
Humans
Receptor, PAR-2
Platelet
Receptor, PAR-1
Platelet activation
Mice, Knockout
biology
Dose-Response Relationship, Drug
Receptors, Purinergic P2
ADCY9
Membrane Proteins
Yohimbine
Cell Biology
Hematology
Peptide Fragments
Receptors, Purinergic P2Y12
Cell biology
Adenosine Diphosphate
Endocrinology
chemistry
Glycoprotein Ib
biology.protein
Receptors, Thrombin
Oligopeptides
Platelet Aggregation Inhibitors
medicine.drug
Adenylyl Cyclases
Signal Transduction
Subjects
Details
- ISSN :
- 00064971
- Volume :
- 99
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....f5c444db58a780fd0abad686d2fd5c7a