A positive feedback loop between glycogen synthase kinase 3β and protein phosphatase 1 after stimulation of NR2B NMDA receptors in forebrain neurons

N-methyl-D-aspartate receptors (NMDARs) are critical for neuronal plasticity and survival, whereas their excessive activation produces excitotoxicity and may accelerate neurodegeneration. Here, we report that stimulation of NMDARs in cultured rat hippocampal or cortical neurons and in the adult mouse brain in vivo disinhibited glycogen synthase kinase 3 beta (GSK3 beta) by protein phosphatase 1(PP1)-mediated dephosphorylation of GSK3 beta at the serine 9 residue. NMDA-triggered GSK3 beta activation was mediated by NMDAR that contained the NR2B subunit. Interestingly, GSK3 beta inhibition reduced inhibitory phosphorylation of the PP1 inhibitor 2 (I2) and attenuated serine 9 dephosphorylation by PP1. These data suggest existence of a feedback loop between GSK3 beta and PP1 that results in amplification of PP1 activation by GSK3 beta. In addition, GSK3 beta inhibition decreased PP1-mediated dephosphorylation of the cAMP-response element-binding protein ( CREB) at the serine 133 residue in NMDA-stimulated neurons. Conversely, overexpression of GSK3 beta abolished non-NR2B-mediated activation of CRE-driven transcription. These data suggest that cross-talk between GSK3 beta and PP1 contributes to NR2B NMDAR-induced inhibition of CREB signaling by non-NR2BNMDAR. The excessive activation of NR2B-PP1-GSK3 beta-PP1 circuitry may contribute to the deficits of CREB-dependent neuronal plasticity in neurodegenerative diseases.