Depolarization of cerebellar granule cells in culture leads to up-regulation of the GABA(A) receptor delta subunit expression. To determine the signaling molecules involved, we examined the effects of protein kinase inhibitors and cyclic AMP-elevating compounds on basal and AMPAR agonist-induced delta mRNA expression in cerebellar granule cells. Treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125 or with pituitary adenylate activating polypeptide increased delta subunit expression by 70%. Selective activation of AMPA receptors with CPW-399 also increased delta mRNA expression (2-4-fold). CPW-399 induction of delta subunit mRNA was reduced by prior treatment with either the MEK1/2 inhibitor U0126 or protein kinase A (PKA) inhibitors KT 5720 and H89. These effects were additive and combined treatment with U0126 and H89 completely prevented induction of delta subunit expression above basal levels. These results suggest that the role of JNK and ERK1/2/PKA on maintainence of delta subunit expression is diammetrically opposite. While JNK activity negatively regulates delta subunit mRNA expression in unstimulated neurons, activity of ERK1/2 and PKA are required for full induction of GABA(A) receptor delta subunit expression in response to AMPA receptor stimulation.