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J. Biol. Chem., Vol. 277, Issue 32, 29321-29329, August 9, 2002

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Development of Platelet Inhibition by cAMP during Megakaryocytopoiesis^*

Els den Dekker, Gertie Gorter, Johan W. M. Heemskerk^§, and Jan-Willem N. Akkerman^¶

From the  Laboratory for Thrombosis and Haemostasis, Department of Haematology, University Medical Center Utrecht and the Institute for Biomembranes, Utrecht University, 3508 GA Utrecht, The Netherlands and the ^§ Department of Biochemistry and Human Biology, Maastricht University, 6200 MD Maastricht, The Netherlands

Prostacyclin is a potent inhibitor of agonist-induced Ca²⁺ increases in platelets, but in the megakaryocytic cell line MEG-01 this inhibition is absent. Using human megakaryocytic cell lines representing different stages in megakaryocyte (Mk) maturation as well as stem cells and immature and mature megakaryocytes, we show that the inhibition by prostacyclin develops at a late maturation stage shortly before platelets are formed. This late appearance is not caused by insufficient cAMP formation or absent protein kinase A (PKA) activity in immature cells. Instead, the appearance of Ca²⁺ inhibition by prostacyclin is accompanied by a sharp increase in the expression of the catalytic subunit of PKA (PKA-C) but not by changes in the expression of the PKA-regulatory subunits I/, II, and II. Overexpression of PKA-C in the megakaryocytic cell line CHRF-288-11 potentiates the Ca²⁺ inhibition by prostacyclin. Thus, up-regulation of PKA-C appears to be a key step in the development of Ca²⁺ inhibition by prostacyclin in platelets.

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