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J Biol Chem ; 279(25): 26266-73, 2004 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-15087444

RESUMO

Shear stress triggers von Willebrand factor (VWF) binding to platelet glycoprotein Ibalpha and subsequent integrin alpha(IIb)beta(3)-dependent platelet aggregation. Concomitantly, nucleotides are released from plateletdense granules, and ADP is known to contribute to shear-induced platelet aggregation (SIPA). We found that the impaired SIPA of platelets from a Hermansky-Pudlak patient lacking dense granules was restored by exogenous l-beta,gamma-methylene ATP, a stable P2X(1) agonist, as well as by ADP, confirming that in addition to ADP (via P2Y(1) and P2Y(12)), ATP (via P2X(1)) also contributes to SIPA. Likewise, SIPA of apyrase-treated platelets was restored upon P2X(1) activation with l-beta,gamma-methylene ATP, which promoted granule centralization within platelets and stimulated P-selectin expression, which is a marker of alpha-granule release. In addition, during SIPA, platelet degranulation required both extracellular Ca(2+) and VWF-glycoprotein Ibalpha interactions without involving alpha(IIb)beta(3). Neither platelet release nor SIPA was affected by protein kinase C inactivation, even though protein kinase C blockade inhibits platelet responses to collagen and thrombin in stirring conditions. In contrast, inhibiting myosin light chain (MLC) kinase with ML-7 reduced platelet release and SIPA by 30%. Accordingly, the potentiating effect of P2X(1) stimulation on the aggregation of apyrase-treated platelets coincided with intensified phosphorylation of MLC and was abrogated by ML-7. SIPA-induced MLC phosphorylation occurred exclusively through released nucleotides and selective antagonism of P2X(1) with MRS2159-reduced SIPA, ATP release, and potently inhibited MLC phosphorylation. We conclude that the P2X(1) ion channel induces MLC-mediated cytoskeletal rearrangements, thus contributing to SIPA and degranulation during VWF-triggered platelet activation.


Assuntos
Trifosfato de Adenosina/metabolismo , Compostos Azo/metabolismo , Cálcio/metabolismo , Calmodulina/química , Quinase de Cadeia Leve de Miosina/metabolismo , Agregação Plaquetária , Complexo Glicoproteico GPIb-IX de Plaquetas/química , Fosfato de Piridoxal/análogos & derivados , Receptores Purinérgicos P2/fisiologia , Fator de von Willebrand/metabolismo , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/química , Compostos Azo/química , Plaquetas/metabolismo , Western Blotting , Colágeno/metabolismo , Citoesqueleto/metabolismo , Ativação Enzimática , Citometria de Fluxo , Humanos , Immunoblotting , Íons , Microscopia Eletrônica , Modelos Biológicos , Selectina-P/biossíntese , Selectina-P/química , Fosforilação , Ativação Plaquetária , Glicoproteínas da Membrana de Plaquetas , Ligação Proteica , Fosfato de Piridoxal/química , Fosfato de Piridoxal/metabolismo , Receptores Purinérgicos P2X , Trombina/metabolismo , Fatores de Tempo
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