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Free Content Effects of plasma membrane Ca2+-ATPase tyrosine phosphorylation on human platelet function

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Summary. 

Background: The plasma membrane Ca2+-ATPase (PMCA) plays an essential role in maintaining low intracellular Ca2+ ([Ca2+]i) in resting platelets. Earlier studies demonstrated that platelet activation by thrombin results in tyrosine phosphorylation of PMCA, which inhibits pump activity. Objectives: The objective was to determine the functional consequences of PMCA tyrosine phosphorylation. Methods: A decapeptide including the tyrosine phosphorylation site of PMCA and a scrambled version were synthesized and introduced into human platelets using saponin. Fura-2 calcium monitoring and aggregometry were used to characterize the effects of inhibition of tyrosine phosphorylation. Results: Western blot analysis of immunoprecipitates showed that introduction of the inhibitory peptide decreased tyrosine phosphorylation of PMCA by nearly 60% in saponin-permeabilized, thrombin-treated platelets as compared with the scrambled control peptide. Concomitant with inhibition of PMCA tyrosine phosphorylation was a significant decrease in [Ca2+]i during thrombin-mediated platelet activation. The functional consequence of reduced PMCA tyrosine phosphorylation and decreased [Ca2+]i was a significant delay in the onset of thrombin-mediated platelet aggregation. Conclusions: The results demonstrate that PMCA tyrosine phosphorylation regulates [Ca2+]i during platelet activation, which affects downstream events in the activation process. Moreover, PMCA tyrosine phosphorylation and resultant inhibition of PMCA activity produces a positive feedback loop mechanism by enhancing the increase in [Ca2+]i accompanying platelet activation.
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Keywords: Ca2+-ATPase; blood platelets; intracellular calcium; phosphorylation; platelet activation

Document Type: Research Article

Publication date: 2007-05-01

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