The relative importance of the ADP receptors, P2Y12 and P2Y1, in thrombin-induced platelet activation

被引：34

作者：

Nylander, S ^{[1
]}

Mattsson, C

Ramström, S

Lindahl, TL

机构：

[1] AstraZeneca R&D, Dept Mol Pharmacol, Preclin R&D, S-43183 Molndal, Sweden

[2] Univ Hosp, Dept Biomed Sci, Div Clin Chem, Linkoping, Sweden

[3] Univ Hosp, Dept Clin Chem, Lab Med Ostergotland, Linkoping, Sweden

来源：

THROMBOSIS RESEARCH | 2003年 / 111卷 / 1-2期

关键词：

P2Y(12); P2Y(1); flow cytometry; platelets; thrombin; ADP;

D O I：

10.1016/j.thromres.2003.08.021

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The objective of this study was to test the relative importance of the two adenosine diphosphate (ADP) receptors P2Y(1) and P2Y(12) in thrombin-induced platelet activation using specific receptor antagonists. Blood from healthy volunteers was incubated with MRS2179, a reversible P2Y(1) antagonist, or AR-C69931, a reversible P2Y(12) antagonist prior to activation with different concentrations of ADP or thrombin. Platelet function in whole blood was assayed by flow cytometry using the antibody PAC-1 to estimate the expression of conformational active alpha(IIb)beta(3), the fibrinogen receptor. Complete inhibition of P2Y(12) or P2Y(1) abolished the ADP response, but only inhibition of P2Y(12) reduced the thrombin-induced response. The relative inhibition of the thrombin response by complete inhibition of P2Y(12) was most pronounced at thrombin concentrations just enough for complete PAR1 cleavage, which is sufficient to release all ADP, giving 70-86% inhibition. Above this concentration, the relative importance of P2Y(12) inhibition decreased due to activation of ADP independent pathways. This study supports P2Y(12) as a drug target compared with P2Y(1). (C) 2003 Elsevier Ltd. All rights reserved.

引用

页码：65 / 73

页数：9

共 31 条

[1] Molecular mapping of thrombin-receptor interactions [J].

Ayala, YM ;

Cantwell, AM ;

Rose, T ;

Bush, LA ;

Arosio, D ;

Di Cera, E .

PROTEINS-STRUCTURE FUNCTION AND GENETICS, 2001, 45 (02) :107-116

[2] Inhibition of platelet function by administration of MRS2179, a P2Y1 receptor antagonist [J].

Baurand, A ;

Raboisson, P ;

Freund, M ;

Léon, C ;

Cazenave, JP ;

Bourguignon, JJ ;

Gachet, C .

EUROPEAN JOURNAL OF PHARMACOLOGY, 2001, 412 (03) :213-221

[3]

CATTANEO M, 1992, BLOOD, V80, P2787

[4] Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding [J].

Cattaneo, M ;

Zighetti, ML ;

Lombardi, R ;

Martinez, C ;

Lecchi, A ;

Conley, PB ;

Ware, J ;

Ruggeri, ZM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (04) :1978-1983

[5] Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores -: Further evidence that some cases of platelet 'primary secretion defect' are heterozygous for a defect of P2CYC receptors [J].

Cattaneo, M ;

Lecchi, A ;

Lombardi, R ;

Gachet, C ;

Zighetti, ML .

ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 2000, 20 (11) :E101-E106

[6] Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets [J].

Covic, L ;

Gresser, AL ;

Kuliopulos, A .

BIOCHEMISTRY, 2000, 39 (18) :5458-5467

[7] Role of the PAR4 thrombin receptor in stabilizing platelet-platelet aggregates as revealed by a patient with Hermansky-Pudlak syndrome [J].

Covic, L ;

Singh, C ;

Smith, H ;

Kuliopulos, A .

THROMBOSIS AND HAEMOSTASIS, 2002, 87 (04) :722-727

[8] Potentiation of thromboxane A2-induced platelet secretion by Gi signaling through the phosphoinositide-3 kinase pathway [J].

Dangelmaier, C ;

Jin, JG ;

Smith, JB ;

Kunapuli, SP .

THROMBOSIS AND HAEMOSTASIS, 2001, 85 (02) :341-348

[9] Differential involvement of the P2Y1 and P2YT receptors in the morphological changes of platelet aggregation [J].

Eckly, A ;

Gendrault, JL ;

Hechler, B ;

Cazenave, JP ;

Gachet, C .

THROMBOSIS AND HAEMOSTASIS, 2001, 85 (04) :694-701

[10] Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs [J].

Foster, CJ ;

Prosser, DM ;

Agans, JM ;

Zhai, Y ;

Smith, MD ;

Lachowicz, JE ;

Zhang, FL ;

Gustafson, E ;

Monsma, FJ ;

Wiekowski, MT ;

Abbondanzo, SJ ;

Cook, DN ;

Bayne, ML ;

Lira, SA ;

Chintala, MS .

JOURNAL OF CLINICAL INVESTIGATION, 2001, 107 (12) :1591-1598

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