The NMDAR subunit NR3A is most highly expressed during the second postnatal week, when synaptogenesis reaches peak levels. Genetic ablation or overexpression of the NR3A subunit negatively interferes with the maturation of cortical synapses and leads to changes in the shape and number of dendritic spines, the density of which is increased in NR3A knock-out mice and decreased in NR3A-overexpressing transgenic mice. Alterations in spine density have been linked to dysregulation of mTOR signaling and synaptic protein translation. Using a yeast two-hybrid system, we identified the mTOR-activating GTPase Rheb as an interacting protein of the NMDAR subunit NR3A. We confirmed the interaction in mammalian cells by expressing recombinant Rheb and NR3A and showed that Rheb and NR3A could be co-immunoprecipitated from synaptic plasma membranes from the developing rat brain. These data suggest that NR3A sequesters synaptic Rheb and might thus function as a break of the mTOR-dependent synaptic translation of protein.
© 2010 S. Karger AG, Basel
- NMDA receptor
- Feldman DE: Synaptic mechanisms for plasticity in neocortex. Annu Rev Neurosci 2009;32:33–55.
- Malenka RC, Bear MF: LTP and LTD: An embarrassment of riches. Neuron 2004;44:5–21.
- Carlisle HJ, Kennedy MB: Spine architecture and synaptic plasticity. Trends Neurosci 2005;28:182–187.
- Hoeffer CA, Klann E: mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci 2010;33:67–75.
- Cavara NA, Hollmann M: Shuffling the deck anew: how NR3A tweaks NMDA receptor function. Mol Neurobiol 2008;38:16–26.
- Cull-Candy S, Brickley S, Farrant M: NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001;11:327–335.
- Wong H-K, Liu X-B, Matos MF, Chan SF, Pérez-Otaño I, Boysen M, Cui J, Nakanishi N, Trimmer JS, Jones EG, Lipton SA, Sucher NJ: Temporal and regional expression of NMDA receptor subunit NR3A in the mammalian brain. J Comp Neurol 2002;450:303–317.
- Zhou C, Jensen F, Sucher N: Altered development of glutamatergic synapses in layer V pyramidal neurons in NR3A knockout mice. Mol Cell Neurosci 2009;42:419–426.
- Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE, Dikkes P, Conner DA, Rayudu PV, Cheung W, Chen HS, Lipton SA, Nakanishi N: Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 1998;393:377–381.
- Roberts AC, Díez-García J, Rodriguiz RM, López IP, Luján R, Martínez-Turrillas R, Picó E, Henson MA, Bernardo DR, Jarrett TM, Clendeninn DJ, López-Mascaraque L, Feng G, Lo DC, Wesseling JF, Wetsel WC, Philpot BD, Pérez-Otaño I: Downregulation of NR3A-containing NMDARs is required for synapse maturation and memory consolidation. Neuron 2009;63:342–356.
- Bassell GJ, Warren ST: Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 2008;60:201–214.
- Bear MF, Dolen G, Osterweil E, Nagarajan N: Fragile X: Translation in action. Neuropsychopharmacology 2008;33:84–87.
- Narayanan U, Nalavadi V, Nakamoto M, Pallas DC, Ceman S, Bassell GJ, Warren ST: FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A. J Neurosci 2007;27:14349–14357.
- Narayanan U, Nalavadi V, Nakamoto M, Thomas G, Ceman S, Bassell GJ, Warren ST: S6k1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. J Biol Chem 2008;283:18478–18482.
- Arsham AM, Neufeld TP: Thinking globally and acting locally with TOR. Curr Opin Cell Biol 2006;18:589–597.
- Chan SF, Sucher NJ: An NMDA receptor signaling complex with protein phosphatase 2a. J Neurosci 2001;21:7985–7992.
- Yamagata K, Sanders LK, Kaufmann WE, Yee W, Barnes CA, Nathans D, Worley PF: Rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel ras-related protein. J Biol Chem 1994;269:16333–16339.
- Aspuria P-J, Tamanoi F: The Rheb family of GTP-binding proteins. Cell Signal 2004;16:1105–1112.
- Ma OK, Sucher NJ: Molecular interaction of NMDA receptor subunit NR3A with protein phosphatase 2A. Neuroreport 2004;15:1447–1450.
- Slabinski L, Jaroszewski L, Rodrigues AP, Rychlewski L, Wilson IA, Lesley SA, Godzik A: The challenge of protein structure determination – lessons from structural genomics. Protein Sci 2007;16:2472–2482.
- Slabinski L, Jaroszewski L, Rychlewski L, Wilson IA, Lesley SA, Godzik A: Xtalpred: a web server for prediction of protein crystallizability. Bioinformatics 2007;23:3403–3405.
- Igarashi Y, Eroshkin A, Gramatikova S, Gramatikoff K, Zhang Y, Smith JW, Osterman AL, Godzik A: Cutdb: a proteolytic event database. Nucleic Acids Res 2007;35:D546–D549.
- Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS: mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010;329:959–964.
- Tang SJ, Schuman EM: Protein synthesis in the dendrite. Philos Trans R Soc Lond B Biol Sci 2002;357:521–529.
- Sharma A, Hoeffer CA, Takayasu Y, Miyawaki T, McBride SM, Klann E, Zukin RS: Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci 2010;30:694–702.
- Weatherill DB, Dyer J, Sossin WS: Ribosomal protein S6 kinase is a critical downstream effector of the target of rapamycin complex 1 for long-term facilitation in aplysia. J Biol Chem 2010;285:12255–12267 .
- Lee MN, Ha SH, Kim J, Koh A, Lee CS, Kim JH, Jeon H, Kim DH, Suh PG, Ryu SH: Glycolytic flux signals to mTOR through glyceraldehyde-3-phosphate dehydrogenase-mediated regulation of Rheb. Mol Cell Biol 2009;29:3991–4001.
Prof. Nikolaus J. Sucher
The Centre for Complementary Medicine Research
University of Western Sydney, Locked Bag 1797
Penrith, NSW 2751 (Australia)
Tel. +61 2 4620 3345, Fax +61 2 4620 3017, E-Mail firstname.lastname@example.org
Received: July 27, 2010
Accepted after revision: October 20, 2010
Published online: December 7, 2010
Number of Print Pages : 7
Number of Figures : 3, Number of Tables : 0, Number of References : 27
Vol. 18, No. 4, Year 2010 (Cover Date: March 2011)
Journal Editor: Ip N.Y. (Hong Kong)
ISSN: 1424-862X (Print), eISSN: 1424-8638 (Online)
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