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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.
Blood. 2002 May 15; 99(10):3629-36.Blood

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.

Authors+Show Affiliations

Department of Physiology and the Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11986217

Citation

Kim, Soochong, et al. "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." Blood, vol. 99, no. 10, 2002, pp. 3629-36.
Kim S, Foster C, Lecchi A, et al. 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. Blood. 2002;99(10):3629-36.
Kim, S., Foster, C., Lecchi, A., Quinton, T. M., Prosser, D. M., Jin, J., Cattaneo, M., & Kunapuli, S. P. (2002). 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. Blood, 99(10), 3629-36.
Kim S, et al. 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. Blood. 2002 May 15;99(10):3629-36. PubMed PMID: 11986217.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Kim,Soochong, AU - Foster,Carolyn, AU - Lecchi,Anna, AU - Quinton,Todd M, AU - Prosser,Dina M, AU - Jin,Jianguo, AU - Cattaneo,Marco, AU - Kunapuli,Satya P, PY - 2002/5/3/pubmed PY - 2002/6/11/medline PY - 2002/5/3/entrez SP - 3629 EP - 36 JF - Blood JO - Blood VL - 99 IS - 10 N2 - 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. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/11986217/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-4971(20)60841-2 DB - PRIME DP - Unbound Medicine ER -