Protease-activated receptors 1 and 4 do not stimulate Gi signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of Gi signaling

Soochong Kim, Carolyn Foster, Anna Lecchi, Todd M. Quinton, Dina M. Prosser, Jianguo Jin, Marco Cattaneo, Satya P. Kunapuli

Research output: Contribution to journalArticle

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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 lb. Because adenosine diphosphate and thromboxane A2 have been shown to cause platelet aggregation by concomitant signaling through Gq and Gi pathways, we investigated whether coactivation of Gq and Gi signaling pathways is the general mechanism by which PAR1 and PAR4 agonists also activate platelet fibrinogen receptor (αIIbβ3). 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; α-thrombin-induced inhibition of adenylyl cyclase was also blocked by Ro 31-8220 or AR-C66096. In platelets from a P2Y12 receptor-defective patient, α-thrombin, SFLLRN, and GYPGKF also failed to inhibit adenylyl cyclase. In platelets from mice lacking the P2Y12 receptor, neither α-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 α-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 Gi signaling pathways and (2) thrombin and thrombin receptor-activating peptides cause platelet aggregation independently of Gi signaling.

Original languageEnglish
Pages (from-to)3629-3636
Number of pages8
JournalBlood
Volume99
Issue number10
DOIs
Publication statusPublished - May 15 2002

Fingerprint

PAR-1 Receptor
Platelets
Platelet Aggregation
Thrombin
Adenosine Diphosphate
Blood Platelets
Agglomeration
Adenylyl Cyclases
Thrombin Receptors
thrombin receptor peptide SFLLRNP
Purinergic P2Y Receptor Antagonists
Fibrinogen Receptors
Thromboxane A2
Platelet Activation
protease-activated receptor 4
Hemostasis
Protein Kinase C
Glycoproteins
Thrombosis
Peptides

ASJC Scopus subject areas

  • Hematology

Cite this

Protease-activated receptors 1 and 4 do not stimulate Gi signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of Gi signaling. / Kim, Soochong; Foster, Carolyn; Lecchi, Anna; Quinton, Todd M.; Prosser, Dina M.; Jin, Jianguo; Cattaneo, Marco; Kunapuli, Satya P.

In: Blood, Vol. 99, No. 10, 15.05.2002, p. 3629-3636.

Research output: Contribution to journalArticle

Kim, Soochong ; Foster, Carolyn ; Lecchi, Anna ; Quinton, Todd M. ; Prosser, Dina M. ; Jin, Jianguo ; Cattaneo, Marco ; Kunapuli, Satya P. / Protease-activated receptors 1 and 4 do not stimulate Gi signaling pathways in the absence of secreted ADP and cause human platelet aggregation independently of Gi signaling. In: Blood. 2002 ; Vol. 99, No. 10. pp. 3629-3636.
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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 lb. Because adenosine diphosphate and thromboxane A2 have been shown to cause platelet aggregation by concomitant signaling through Gq and Gi pathways, we investigated whether coactivation of Gq and Gi signaling pathways is the general mechanism by which PAR1 and PAR4 agonists also activate platelet fibrinogen receptor (αIIbβ3). 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; α-thrombin-induced inhibition of adenylyl cyclase was also blocked by Ro 31-8220 or AR-C66096. In platelets from a P2Y12 receptor-defective patient, α-thrombin, SFLLRN, and GYPGKF also failed to inhibit adenylyl cyclase. In platelets from mice lacking the P2Y12 receptor, neither α-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 α-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 Gi signaling pathways and (2) thrombin and thrombin receptor-activating peptides cause platelet aggregation independently of Gi signaling.",
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AU - Foster, Carolyn

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AU - Quinton, Todd M.

AU - Prosser, Dina M.

AU - Jin, Jianguo

AU - Cattaneo, Marco

AU - Kunapuli, Satya P.

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