Cross-Talk in Nucleotide Signaling in Glioma C6 Cells

The chapter is focused on the mechanism of action of metabotropic P2Y nucleotide receptors: P2Y₁, P2Y₂, P2Y₁₂, P2Y₁₄ and the ionotropic P2X₇ receptor in glioma C6 cells. P2Y₁ and P2Y₁₂ both respond to ADP, but while P2Y₁ links to PLC and elevates cytosolic Ca²⁺ concentration, P2Y₁₂ 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 P2Y₁ receptor strongly decreases and P2Y₁₂ becomes a major player responsible for ADP-evoked signal transduction. The P2Y₁₂ receptor activates ERK1/2 kinase phosphorylation (a known cell proliferation regulator) and stimulates Akt activity, contributing to glioma invasiveness. In contrast, P2Y₁ has an inhibitory effect on Akt pathway signaling. Furthermore, the P2X₇ receptor, often responsible for apoptotic fate, is not involved in Ca²⁺elevation in C6 cells. The shift in nucleotide receptor expression from P2Y₁ to P2Y₁₂ during serum withdrawal, the cross talk between both receptors and the lack of P2X₇ activity shows the precise self-regulating mechanism, enhancing survival and preserving the neoplastic features of C6 cells.