The ATP-gated P2X1 Receptor Plays a Pivotal Role in Activation of Aspirin-treated Platelets by Thrombin and Epinephrine

摘要: Human platelets express protease-activated receptor 1 (PAR1) and PAR4 but limited data indicate for differences in signal transduction. We studied the involvement of PAR1 cross-talk between thrombin epinephrine. The results show that epinephrine acted via α2A-adrenergic receptors to provoke aggregation, secretion, Ca2+ mobilization aspirin-treated pre-stimulated with subthreshold concentrations thrombin. Incubating antibodies against or PAR4-specific inhibitor pepducin P4pal-i1 abolished aggregation. Furthermore, pre-exposed PAR4-activating peptide AYPGKF, not PAR1-activating SFLLRN, were aggregated by epinephrine, whereas both AYPGKF SFLLRN synergized absence aspirin. roles released ATP ADP elucidated using antagonists purinergic P2X1, P2Y1, P2Y12 (i.e. NF449, MRS2159, MRS2179, cangrelor). Intriguingly, ATP, ADP, was required epinephrine/thrombin-induced In Western blot analysis, a low concentration stimulated phosphorylation Akt on serine 473. Moreover, phosphatidyl inositide 3-kinase LY294002 antagonized effect combined AYPGKF. Thus, platelets, PAR4, PAR1, interacts synergistically receptors, PI3-kinase/Akt pathway is involved this cross-talk. PAR4-pretreated caused dense granule subsequent signaling from ATP-gated P2X1-receptor induced These suggest new mechanism has as key element circumvents action aspirin epinephrine-facilitated PAR4-mediated platelet activation.