Ba. Hechler et al., MpI ligand increases P2Y1 receptor gene expression in megakaryocytes with no concomitant change in platelet response to ADP, MOLEC PHARM, 60(5), 2001, pp. 1112-1120
AV6The P2Y(1) receptor is responsible for the initiation of platelet aggreg
ation 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 me
gakaryocytic cell line Y10/L8057, we detected P2Y(1) 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 th
eir expression of differentiation markers. MpI ligand enhanced levels of P2
Y(1) mRNAs in Y10/L8057 cells and this effect was selective: the same cytok
ine did not increase levels of A2a adenosine receptor mRNA. Although Mpl li
gand did not affect the short half-lives of the P2Y(1) mRNAs, it enhanced t
ranscription of the P2Y, gene. It also increased cell size and the number o
f cell surface P2Y(1) receptors, but not P2Y(1) receptor density. Injection
of Mpl ligand into mice upregulated P2Y(1) receptor mRNAs in megakaryocyte
s, as shown by in situ hybridization. However, platelets isolated from thes
e mice did not exhibit a higher P2Y(1) receptor density or increased reacti
vity to AIDP. This correlates with the finding that MpI ligand increases GP
IIb mRNA in megakaryocytes but not the density of the protein per platelet.
Thus, the enhancement of P2Y(1) receptor expression induced by MpI ligand
in megakaryocytes may be an integral feature of their differentiation, wher
eas clinical use of this compound might not be associated with platelet hyp
er-reactivity to ADP.