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The Journal of Neuroscience, December 26, 2007, 27(52):14349-14357; doi:10.1523/JNEUROSCI.2969-07.2007

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Neurobiology of Disease
FMRP Phosphorylation Reveals an Immediate-Early Signaling Pathway Triggered by Group I mGluR and Mediated by PP2A

Usha Narayanan,¹ Vijayalaxmi Nalavadi,² Mika Nakamoto,¹ David C. Pallas,^3,5 Stephanie Ceman,⁶ Gary J. Bassell,² and Stephen T. Warren^1,3,4

Departments of ¹Human Genetics, ²Cell Biology, ³Biochemistry, and ⁴Pediatrics and ⁵Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, and ⁶Department of Cell and Developmental Biology, University of Illinois, Urbana-Champaign, Illinois 61801

Correspondence should be addressed to Stephen T. Warren at the above address. Email: swarren{at}emory.edu

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.

Key words: FMRP; fragile X; phosphorylation; mGluR; synaptic plasticity; PP2A

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Received June 29, 2007; revised Nov. 2, 2007; accepted Nov. 13, 2007.

Correspondence should be addressed to Stephen T. Warren at the above address. Email: swarren{at}emory.edu

This article has been cited by other articles:

				B. E. Pfeiffer and K. M. Huber The State of Synapses in Fragile X Syndrome Neuroscientist, October 1, 2009; 15(5): 549 - 567. [Abstract] [PDF]

				J. Schutt, K. Falley, D. Richter, H.-J. Kreienkamp, and S. Kindler Fragile X Mental Retardation Protein Regulates the Levels of Scaffold Proteins and Glutamate Receptors in Postsynaptic Densities J. Biol. Chem., September 18, 2009; 284(38): 25479 - 25487. [Abstract] [Full Text] [PDF]

				A.-M. J. Cziko, C. T. McCann, I. C. Howlett, S. A. Barbee, R. P. Duncan, R. Luedemann, D. Zarnescu, K. E. Zinsmaier, R. R. Parker, and M. Ramaswami Genetic Modifiers of dFMR1 Encode RNA Granule Components in Drosophila Genetics, August 1, 2009; 182(4): 1051 - 1060. [Abstract] [Full Text] [PDF]

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				J. A. Ronesi and K. M. Huber Metabotropic Glutamate Receptors and Fragile X Mental Retardation Protein: Partners in Translational Regulation at the Synapse Sci. Signal., February 5, 2008; 1(5): pe6 - pe6. [Abstract] [Full Text] [PDF]

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