Molecular determinants of P2Y(2) nucleotide receptor function - Implications for proliferative and inflammatory pathways in astrocytes

In the mammalian nervous system, P2 nucleotide receptors mediate neurotransmission, release of proinflammatory cytokines, and reactive astrogliosis. Extracellular nucleotides activate multiple P2 receptors in neurons and glial cells, including G protein-coupled P2Y receptors and P2X receptors, which are ligand-gated ion channels. In glial cells, the P2Y(2) receptor subtype, distinguished by its ability to be equipotently activated by ATP and UTP, is coupled to pro-inflammatory signaling pathways. In situ hybridization studies with rodent brain slices indicate that P2Y(2) receptors are expressed primarily in the hippocampus and cerebellum. Astrocytes express several P2 receptor subtypes, including P2Y(2) receptors whose activation stimulates cell proliferation and migration. P2Y(2) receptors, via an RGD (Arg-Gly-Asp) motif in their first extracellular loop, bind to alpha(v)beta(3)/beta(5) integrins, whereupon P2Y(2) receptor activation stimulates integrin signaling pathways that regulate cytoskeletal reorganization and cell motility. The C-terminus of the P2Y(2) receptor contains two Src-homology-3 (SH3)-binding domains that upon receptor activation, promote association with Src and transactivation of growth factor receptors. Together, our results indicate that P2Y(2) receptors complex with both integrins and growth factor receptors to activate multiple signaling pathways. Thus, P2Y(2) receptors present novel targets to control reactive astrogliosis in neurodegenerative diseases.