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|Title:||Extracellular Ca(2+) modulates ADP-evoked aggregation through altered agonist degradation: implications for conditions used to study P2Y receptor activation.|
Evans, R. J.
Mahaut-Smith, M. P.
|Citation:||British Journal of Haematology, 2011, 153 (1), pp. 83-91|
|Abstract:||ADP is considered a weak platelet agonist due to the limited aggregation responses it induces in vitro at physiological concentrations of extracellular Ca(2+) [(Ca(2+) )(o) ]. Lowering [Ca(2+) ](o) paradoxically enhances ADP-evoked aggregation, an effect that has been attributed to enhanced thromboxane A(2) production. This study examined the role of ectonucleotidases in the [Ca(2+) ](o) -dependence of platelet activation. Reducing [Ca(2+) ](o) from millimolar to micromolar levels converted ADP (10 μmol/l)-evoked platelet aggregation from a transient to a sustained response in both platelet-rich plasma and washed suspensions. Blocking thromboxane A(2) production with aspirin had no effect on this [Ca(2+) ](o) -dependence. Prevention of ADP degradation abolished the differences between low and physiological [Ca(2+) ](o) resulting in a robust and sustained aggregation in both conditions. Measurements of extracellular ADP revealed reduced degradation in both plasma and apyrase-containing saline at micromolar compared to millimolar [Ca(2+) ](o) . As reported previously, thromboxane A(2) generation was enhanced at low [Ca(2+) ](o) , however this was independent of ectonucleotidase activity(.) P2Y receptor antagonists cangrelor and MRS2179 demonstrated the necessity of P2Y(12) receptors for sustained ADP-evoked aggregation, with a minor role for P2Y(1) . In conclusion, Ca(2+) -dependent ectonucleotidase activity is a major factor determining the extent of platelet aggregation to ADP and must be controlled for in studies of P2Y receptor activation.|
|Rights:||Copyright © 2011 Blackwell Publishing Ltd. Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopen#OnlineOpen_Terms|
|Appears in Collections:||Published Articles, Dept. of Cell Physiology and Pharmacology|
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