AMPAR signaling mediating GABAAR δ subunit up-regulation in cultured mouse cerebellar granule cells

Depolarization of cerebellar granule cells in culture leads to up-regulation of the GABAA receptor δ 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 δ mRNA expression in cerebellar granule cells. Treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125 or with pituitary adenylate activating polypeptide increased δ subunit expression by 70%. Selective activation of AMPA receptors with CPW-399 also increased δ mRNA expression (2–4-fold). CPW-399 induction of δ 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 δ subunit expression above basal levels. These results suggest that the role of JNK and ERK1/2/PKA on maintainence of δ subunit expression is diammetrically opposite. While JNK activity negatively regulates δ subunit mRNA expression in unstimulated neurons, activity of ERK1/2 and PKA are required for full induction of GABAA receptor δ subunit expression in response to AMPA receptor stimulation.