FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A

• Authors: Usha Narayanan, Emory University; Vijayalaxmi Nalavadi, Emory University; Mika Nakamoto, Emory University; David C. Pallas, Emory University; Stephen Warren, Emory University; Gary Bassell, Emory University; Stephanie Ceman, University of Illinois
• Journal Title: Journal of Neuroscience
• Volume: Volume 27, Number 52
• Publisher: Society for Neuroscience | 2007-12-26, Pages 14349-14357
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1523/JNEUROSCI.2969-07.2007
• Subjects: Biology, Genetics; Chemistry, Biochemistry
• Keywords: Science & Technology; Life Sciences & Biomedicine; Neurosciences; Neurosciences & Neurology; fMRP; fragile X; phosphorylation; mGluR; synaptic plasticity; PP2A; X MENTAL-RETARDATION; PROTEIN PHOSPHATASE 2A; METABOTROPIC GLUTAMATE RECEPTORS; LONG-TERM DEPRESSION; MESSENGER-RNA; MOUSE MODEL; TRANSLATING POLYRIBOSOMES; DEPENDENT TRANSLATION; SYNAPTIC PLASTICITY; OKADAIC ACID

Abstract

Fragile X syndrome is a common form of inherited mental retardation and is caused by loss of fragile X mental retardation protein (FMRP), a selective RNA-binding protein that influences the translation of target messages. Here, we identify protein phosphatase 2A (PP2A) as an FMRP phosphatase and report rapid FMRP dephosphorylation after immediate group I metabotropic glutamate receptor (mGluR) stimulation (<1 min) in neurons caused by enhanced PP2A enzymatic activity. In contrast, extended mGluR activation (1-5 min) resulted in mammalian target of rapamycin (mTOR)-mediated PP2A suppression and FMRP rephosphorylation. These activity-dependent changes in FMRP phosphorylation were also observed in dendrites and showed a temporal correlation with the translational profile of select FMRP target transcripts. Collectively, these data reveal an immediate-early signaling pathway linking group I mGluR activity to rapid FMRP phosphorylation dynamics mediated by mTOR and PP2A.