Abstract
The P2Y1 receptor is responsible for the initiation of platelet aggregation in response to ADP and plays a key role in thrombosis. Although this receptor is expressed early in the platelet lineage, the regulation of its expression during megakaryocyte differentiation is unknown. In the mouse megakaryocytic cell line Y10/L8057, we detected P2Y1 mRNA of three sizes (2.5, 4.4, and 7.4 kb). These cells have previously been shown to respond to Mpl ligand, the pivotal regulator of megakaryocytopoiesis, by increasing their expression of differentiation markers. Mpl ligand enhanced levels of P2Y1 mRNAs in Y10/L8057 cells and this effect was selective: the same cytokine did not increase levels of A2a adenosine receptor mRNA. Although Mpl ligand did not affect the short half-lives of the P2Y1 mRNAs, it enhanced transcription of theP2Y1 gene. It also increased cell size and the number of cell surface P2Y1 receptors, but not P2Y1 receptor density. Injection of Mpl ligand into mice up-regulated P2Y1 receptor mRNAs in megakaryocytes, as shown by in situ hybridization. However, platelets isolated from these mice did not exhibit a higher P2Y1 receptor density or increased reactivity to ADP. This correlates with the finding that Mpl ligand increases GPIIb mRNA in megakaryocytes but not the density of the protein per platelet. Thus, the enhancement of P2Y1receptor expression induced by Mpl ligand in megakaryocytes may be an integral feature of their differentiation, whereas clinical use of this compound might not be associated with platelet hyper-reactivity to ADP.
- The American Society for Pharmacology and Experimental Therapeutics
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