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

• Type of Material: Article
• 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
• Language: English
• Date: 2007-12-26
• Publisher: Society for Neuroscience
• Publication Version: Final Published Version
• Copyright Statement: © 2007 Society for Neuroscience. CC BY 4.0
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.2969-07.2007
• Title of Journal or Parent Work: Journal of Neuroscience
• ISSN: 0270-6474
• Volume: 27
• Issue: 52
• Start Page: 14349
• End Page: 14357
• Grant/Funding Information: This work was supported by National Institutes of Health Grant HD20521 (S.T.W.), Baylor-Emory Fragile X Center Grants HD24064 (S.T.W.), CA57327 (D.C.P.), NS051127 (G.J.B.), and HD41591 (S.C.), and a FRAXA postdoctoral fellowship (U.N.).
• Keywords: PP2A; TRANSLATING POLYRIBOSOMES; mGluR; phosphorylation; Neurosciences & Neurology; DEPENDENT TRANSLATION; METABOTROPIC GLUTAMATE RECEPTORS; fMRP; Science & Technology; LONG-TERM DEPRESSION; Neurosciences; OKADAIC ACID; fragile X; SYNAPTIC PLASTICITY; PROTEIN PHOSPHATASE 2A; MESSENGER-RNA; MOUSE MODEL; Life Sciences & Biomedicine; X MENTAL-RETARDATION; synaptic plasticity
• Research Categories: Chemistry, Biochemistry; Biology, Genetics

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.