We characterized the expression and functional properties of the ADP‐sensitive P2Y₁ and P2Y₁₂ nucleotide receptors in glioma C6 cells cultured in medium devoid of serum for up to 96 h. During this long‐term serum starvation, cell morphology changed from fibroblast‐like flat to round, the adhesion pattern changed, cell‐cycle arrest was induced, extracellular signal‐regulated kinase (ERK1/2) phosphorylation was reduced, Akt phosphorylation was enhanced, and expression of the P2Y₁₂ receptor relative to P2Y₁ was increased. These processes did not reflect differentiation into astrocytes or oligodendrocytes, as expression of glial fibrillary acidic protein and NG2 proteoglycan (standard markers of glial cell differentiation) was not increased during the serum deprivation. Transfer of the cells into fresh medium containing 10% fetal bovine serum reversed the changes. This demonstrates that serum starvation caused only temporary growth arrest of the glioma C6 cells, which were ready for rapid division as soon as the environment became more favorable. In cells starved for 72 and 96 h, expression of the P2Y₁ receptor was low, and the P2Y₁₂ receptor was the major player, responsible for ADP‐evoked signal transduction. The P2Y₁₂ receptor activated ERK1/2 kinase phosphorylation (a known cell proliferation regulator) and stimulated Akt activity. These effects were reduced by AR‐C69931MX, a specific antagonist of the P2Y₁₂ receptor. On the other hand, Akt phosphorylation increased in parallel with the low expression of the P2Y₁ receptor, indicating the inhibitory role of P2Y₁ in Akt pathway signaling. The shift in nucleotide receptor expression from P2Y₁ to P2Y₁₂ would appear to be a new and important self‐regulating mechanism that promotes cell growth rather than differentiation and is a defense mechanism against effects of serum deprivation.