Identification of A New Pharmacological Modulator for P2Y2 Receptor Activity

Abstract

P2Y2 is a G-protein-coupled membrane receptor activated by ATP or UTP nucleotides. They play major roles in cellular physiology in different aspects including inflammatory responses and apoptosis. Therefore, P2Y2 receptor is considered to be a potential therapeutic target for regression of vascular inflammation. Various UTP modifications have been developed in order to increase their selectivity and stability. Here, we observed that aminoallyl-UTP is a cell-specific biased ligand for P2Y2 receptor. Interestingly, aminoallyl-UTP mediated Ca2+ signaling only in hP2Y2-transfected 1321N1 astrocytoma cells in a dose-dependent manner, but not in HCAEC and HeLa cells which express a high level of endogenous P2Y2 receptor. Aminoallyl-UTP-activated P2Y2 receptors were seen to increase phosphorylation of Akt, but with no effect on MAPK pathways, whereas UTP inhibits Akt phosphorylation and activates MAPK pathways in HCAEC. Our study provides new evidence that the P2Y2 receptor can be pharmacologically manipulated to target desired pathways in a cell-specific manner.