Cross-talk in nucleotide signaling in glioma C6 cells.

The chapter is focused on the mechanism of action of metabotropic P2Y nucleotide receptors: P2Y(1), P2Y(2), P2Y(12), P2Y(14) and the ionotropic P2X(7) receptor in glioma C6 cells. P2Y(1) and P2Y(12) both respond to ADP, but while P2Y(1) links to PLC and elevates cytosolic Ca(2+) concentration, P2Y(12) negatively couples to adenylate cyclase, maintaining cAMP at low level. In glioma C6, these two P2Y receptors modulate activities of ERK1/2 and PI3K/Akt signaling and the effects depend on physiological conditions of the cells. During prolonged serum deprivation, cell growth is arrested, the expression of the P2Y(1) receptor strongly decreases and P2Y(12) becomes a major player responsible for ADP-evoked signal transduction. The P2Y(12) receptor activates ERK1/2 kinase phosphorylation (a known cell proliferation regulator) and stimulates Akt activity, contributing to glioma invasiveness. In contrast, P2Y(1) has an inhibitory effect on Akt pathway signaling. Furthermore, the P2X(7) receptor, often responsible for apoptotic fate, is not involved in Ca(2+)elevation in C6 cells. The shift in nucleotide receptor expression from P2Y(1) to P2Y(12) during serum withdrawal, the cross talk between both receptors and the lack of P2X(7) activity shows the precise self-regulating mechanism, enhancing survival and preserving the neoplastic features of C6 cells.