Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes

Page, Guylène; Khidir, Fuad Al; Pain, Stéphanie; Barrier, Laurence; Fauconneau, Bernard; Guillard, Olivier; Piriou, Alain; Hugon, Jacques

doi:10.1016/j.neuint.2006.01.020

Cited by 69 publications

(59 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To understand the implications of S6K1 phosphorylation of FMRP in the context of neuronal activity, we first confirmed previous reports of S6K1 activation by group I mGluR-mediated ERK1/2 and mTOR pathways (15,20,31,32). Indeed S6K1 phosphorylation on serine 421/424 (23) was observed in primary neurons treated with DHPG, a group I mGluR agonist using untreated neurons as control (Fig.…”

Section: Resultssupporting

confidence: 82%

See 1 more Smart Citation

S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade

Narayanan

Nalavadi

Nakamoto

et al. 2008

Journal of Biological Chemistry

195

229

View full text Add to dashboard Cite

Fragile X syndrome is a common form of cognitive deficit caused by the functional absence of fragile X mental retardation protein (FMRP), a dendritic RNA-binding protein that represses translation of specific messages. Although FMRP is phosphorylated in a group I metabotropic glutamate receptor (mGluR) activity-dependent manner following brief protein phosphatase 2A (PP2A)-mediated dephosphorylation, the kinase regulating FMRP function in neuronal protein synthesis is unclear. Here we identify ribosomal protein S6 kinase (S6K1) as a major FMRP kinase in the mouse hippocampus, finding that activity-dependent phosphorylation of FMRP by S6K1 requires signaling inputs from mammalian target of rapamycin (mTOR), ERK1/2, and PP2A. Further, the loss of hippocampal S6K1 and the subsequent absence of phospho-FMRP mimic FMRP loss in the increased expression of SAPAP3, a synapse-associated FMRP target mRNA. Together these data reveal a S6K1-PP2A signaling module regulating FMRP function and place FMRP phosphorylation in the mGluR-triggered signaling cascade required for proteinsynthesis-dependent synaptic plasticity.Fragile X syndrome is the most common form of inherited mental retardation and is caused by a functional absence of the RNA-binding protein, fragile X mental retardation protein, FMRP.3 The protein, FMRP, is known to associate with ϳ3% of the mammalian brain mRNAs, repressing their translation; many of these target mRNAs indeed appear overtranslated in the absence of FMRP (1). Electrophysiology of the fragile X mouse model has revealed a synaptic deficit in the hippocampus with elevated group I metabotropic glutamate receptor (mGluR)-mediated long term depression. Accordingly, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization is enhanced in the absence of FMRP, all thought due to constitutive overtranslation of an long-term depression (LTD)-required FMRP target mRNA(s) (2-4). Group I mGluR activity is also known to influence FMRP transport and synthesis (5, 6); however, little is known about regulation of FMRP itself.Post-translational modifications are known regulators of activity-dependent protein synthesis (7), and FMRP is known to be phosphorylated at a highly conserved serine at position 499. The effects of FMRP phosphorylation on translation by ribosomal run-off assays suggested that non-phosphorylated FMRP associates with actively translating ribosomes, whereas phosphorylated FMRP is found in the context of potentially stalled ribosomes (8). We recently determined that FMRP is dephosphorylated by protein phosphatase 2A (PP2A) and, immediately following mGluR stimulation, PP2A dephosphorylates FMRP, corresponding with the translation of SAPAP3, an FMRP target mRNA (9). SAPAP3 is a post-synaptic scaffolding protein associated with PSD95, whose message was previously identified as an FMRP target mRNA in the mouse brain following FMRP immunoprecipitation and microchip analyses (10,35,36). Less than 2 min following mGluR activation, FMRP is rephosphorylated in a PP2A-and mamm...

show abstract

Section: Resultssupporting

confidence: 82%

“…S5). Since mGluR-triggered mTOR and ERK1/2 pathways are known to converge on S6K1 (20), these data suggest that mGluR-dependent S6K1 phosphorylation of FMRP occurs following the convergence of ERK1/2 and mTOR signals on S6K1.…”

Section: Resultsmentioning

confidence: 78%

S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade

Narayanan

Nalavadi

Nakamoto

et al. 2008

Journal of Biological Chemistry

195

229

View full text Add to dashboard Cite

show abstract

“…A small but significant increase in protein synthesis was induced by DHPG ( p Ͻ 0.05) in the presence of rapamycin, compared with rapamycin alone, although this failed to even reach "no-drug" basal levels. These data are in agreement with previous studies showing that Group I mGluR activation increases synaptic translation (Weiler et al, 1996;Huber et al, 2000) and suggest that DHPG-induced protein synthesis is dependent on both a rapamycin-sensitive mTOR pathway and an alternative pathway (Gallagher et al, 2004;Page et al, 2006).…”

Section: Group I Mglur-activated Protein Synthesis Is Camkii Dependentsupporting

confidence: 93%

Calcium/Calmodulin-Dependent Protein Kinase II Mediates Group I Metabotropic Glutamate Receptor-Dependent Protein Synthesis and Long-Term Depression in Rat Hippocampus

Mockett¹,

Guévremont²,

Wutte³

et al. 2011

J. Neurosci.

117

View full text Add to dashboard Cite

Activation of Group I metabotropic glutamate receptors (mGluRs) in rat hippocampus induces a form of long-term depression (LTD) that is dependent on protein synthesis. However, the intracellular mechanisms leading to the initiation of protein synthesis and expression of LTD after mGluR activation are only partially understood. We investigated the role of several pathways linked to mGluR activation, translation initiation, and induction of LTD. We found that Group I mGluR-dependent protein synthesis and associated LTD, as induced by the agonist (RS)-3,5-dihydrophenylglycine (DHPG) or paired-pulse synaptic stimulation, was dependent on activation of calcium/

show abstract

“…Stimulation of the mGluR5 receptors by dihydroxyphenylglycine (DHPG) leads to LTD, which requires postsynaptic translation of preexisting dendritically localized mRNA (Huber et al 2001). Recent reports have shown that mGluR1 leads to increased activation of the mTOR/S6K pathway via ERK in both hippocampus and striatum (Page et al 2006). However, a recent study has shown that S6K is not required for the mGluR-LTD (Antion et al 2008a).…”

Section: Translation Control By Neurotransmittersmentioning

confidence: 99%

Consolidation and translation regulation: Figure 1.

et al. 2012

View full text Add to dashboard Cite

mRNA translation, or protein synthesis, is a major component of the transformation of the genetic code into any cellular activity. This complicated, multistep process is divided into three phases: initiation, elongation, and termination. Initiation is the step at which the ribosome is recruited to the mRNA, and is regarded as the major rate-limiting step in translation, while elongation consists of the elongation of the polypeptide chain; both steps are frequent targets for regulation, which is defined as a change in the rate of translation of an mRNA per unit time. In the normal brain, control of translation is a key mechanism for regulation of memory and synaptic plasticity consolidation, i.e., the off-line processing of acquired information. These regulation processes may differ between different brain structures or neuronal populations. Moreover, dysregulation of translation leads to pathological brain function such as memory impairment. Both normal and abnormal function of the translation machinery is believed to lead to translational up-regulation or down-regulation of a subset of mRNAs. However, the identification of these newly synthesized proteins and determination of the rates of protein synthesis or degradation taking place in different neuronal types and compartments at different time points in the brain demand new proteomic methods and system biology approaches. Here, we discuss in detail the relationship between translation regulation and memory or synaptic plasticity consolidation while focusing on a model of cortical-dependent taste learning task and hippocampal-dependent plasticity. In addition, we describe a novel systems biology perspective to better describe consolidation.

show abstract

Group I metabotropic glutamate receptors activate the p70S6 kinase via both mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK 1/2) signaling pathways in rat striatal and hippocampal synaptoneurosomes

Cited by 69 publications

References 60 publications

S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade

S6K1 Phosphorylates and Regulates Fragile X Mental Retardation Protein (FMRP) with the Neuronal Protein Synthesis-dependent Mammalian Target of Rapamycin (mTOR) Signaling Cascade

Calcium/Calmodulin-Dependent Protein Kinase II Mediates Group I Metabotropic Glutamate Receptor-Dependent Protein Synthesis and Long-Term Depression in Rat Hippocampus

Consolidation and translation regulation: Figure 1.

Contact Info

Product

Resources

About