Stimulation of the receptor has a trophic effect on differentiating cerebellar granule cells

Balázs, R.; Hack, N.; J∅rgensen, Ole Steen

doi:10.1016/0304-3940(88)90149-8

Cited by 216 publications

(62 citation statements)

References 21 publications

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“…Data from an increasing number of laboratories have demonstrated roles for EAA receptors in general, and the NMDA receptor in particular, in the development of neural circuits. For example, EAA receptors regulate neurite outgrowth in hippocampal neurons (Mattson et al, 1988a) and promote survival of cerebellar neurons (Balazs et al, 1988). The EAA receptors apparently play a major role in the process of synapse formation in many brain regions including the visual system (Kleinschmidt et al, 1987;Cline et al, 1990) and hippocampus (Mattson et al, 1988b).…”

Section: Discussionmentioning

confidence: 99%

Basic FGF regulates the expression of a functional 71 kDa NMDA receptor protein that mediates calcium influx and neurotoxicity in hippocampal neurons

Mattson¹,

Kumar²,

Wang³

et al. 1993

J. Neurosci.

194

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Basic fibroblast growth factor (bFGF) was recently found to modulate the outgrowth-regulating effects of glutamate, and protected neurons from several brain regions against excitotoxi/ischemic damage. We provide evidence that the excitoprotective mechanism of bFGF involves suppression of the expression of a 71 kDa NMDA receptor protein (NMDARP- 71). NMDARP-71 protein and mRNA levels were reduced in neurons in bFGF- treated hippocampal cell cultures. The levels of the NMDARP-71 were not reduced by NGF or epidermal growth factor, and bFGF did not reduce the level of mRNA for the GluR1 kainate/AMPA receptor, demonstrating the specificity of the effect of bFGF on the NMDARP-71. The reduction in NMDARP-71 expression in bFGF-treated neurons was correlated with reduced vulnerability to NMDA neurotoxicity. A major role for NMDARP-71 in calcium responses to NMDA and excitotoxicity was demonstrated using antisense oligonucleotides directed against NMDARP-71. Northern and Western blot analysis and immunocytochemistry showed that NMDARP-71 antisense oligonucleotides caused a selective suppression of NMDARP-71 mRNA and protein levels during 12–44 hr exposure periods. Elevations in intracellular calcium levels normally caused by glutamate and NMDA were attenuated in neurons exposed to NMDARP-71 antisense oligonucleotide; calcium responses to kainate were relatively unaffected. NMDARP-71 antisense oligonucleotides protected the neurons against excitotoxicity. Thus, NMDARP-71 is a necessary component of an NMDA receptor mediating calcium responses and neurotoxicity in hippocampal neurons. Taken together, these data identify a mechanism whereby bFGF can modify neuronal responses to glutamate, and suggest that regulating the expression of excitatory amino acid receptors may provide a means for growth factors to influence the plasticity and degeneration of neural circuits.

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Section: Discussionmentioning

confidence: 99%

Basic FGF regulates the expression of a functional 71 kDa NMDA receptor protein that mediates calcium influx and neurotoxicity in hippocampal neurons

Mattson¹,

Kumar²,

Wang³

et al. 1993

J. Neurosci.

194

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“…Exposure to low concentrations of glutamate induces neuroprotective effects in dispersed neuronal cultures (Balazs et al, 1988;Bambrick et al, 1995;Hardingham et al, 2002;Jiang et al, 2005;Soriano et al, 2006). In contrast, high concentrations of glutamate trigger excitotoxicity in cultured neurons (Michaels and Rothman, 1990;Westbrook, 1993;Choi, 1994;Ankarcrona et al, 1995;Raymond et al, 1996).…”

Section: Technical Approaches and Considerationsmentioning

confidence: 99%

Biphasic Coupling of Neuronal Nitric Oxide Synthase Phosphorylation to the NMDA Receptor Regulates AMPA Receptor Trafficking and Neuronal Cell Death

Rameau¹,

Tukey²,

Garcin³

et al. 2007

J. Neurosci.

148

130

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Postsynaptic nitric oxide (NO) production affects synaptic plasticity and neuronal cell death. Ca 2ϩ fluxes through the NMDA receptor (NMDAR) stimulate the production of NO by neuronal nitric oxide synthase (nNOS). However, the mechanisms by which nNOS activity is regulated are poorly understood. We evaluated the effect of neuronal stimulation with glutamate on the phosphorylation of nNOS. We show that, in cortical neurons, a low glutamate concentration (30 M) induces rapid and transient NMDAR-dependent phosphorylation of S1412 by Akt, followed by sustained phosphorylation of S847 by CaMKII (calcium-calmodulin-dependent kinase II). We demonstrate that phosphorylation of S1412 by Akt is necessary for activation of nNOS by the NMDAR. nNOS mutagenesis confirms that these phosphorylations respectively activate and inhibit nNOS and, thus, transiently activate NO production. A constitutively active (S1412D), but not a constitutively repressed (S847D) nNOS mutant elevated surface glutamate receptor 2 levels, demonstrating that these phosphorylations can control AMPA receptor trafficking via NO. Notably, an excitotoxic stimulus (150 M glutamate) induced S1412, but not S847 phosphorylation, leading to deregulated nNOS activation. S1412D did not kill neurons; however, it enhanced the excitotoxicity of a concomitant glutamate stimulus. We propose a swinging domain model for the regulation of nNOS: S1412 phosphorylation facilitates electron flow within the reductase module of nNOS, increasing nNOS sensitivity to Ca 2ϩ -calmodulin. These findings suggest a critical role for a kinetically complex and novel series of regulatory nNOS phosphorylations induced by the NMDA receptor for the in vivo control of nNOS.

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“…These postnatal cerebellar cultures contain cerebellar granule neurons and their precursors, other cerebellar interneurons, and cerebellar glia (Trenkner,199 1). Some aspects of the development and differentiation of granule neurons occur in these postnatal cerebellar cultures and can be modified by the addition of extracellular factors (Balazs et al, 1988a;Hatten et al, 1988;Kingsbury et al, 1989;Messer, 1989;Gao et al, 199 1;Trenkner, 199 1). We are interested in learning whether conditions that modify differentiation ofthese cells also alter expression of identified homeobox genes.…”

Section: Poulhomeoboxmentioning

confidence: 99%

NMDA receptor activation in differentiating cerebellar cell cultures regulates the expression of a new POU gene, Cns-1

et al. 1994

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POU/homeobox genes encode transcription regulatory proteins that are important in defining cellular phenotypes. Expression of these genes may be critical for to the regulation of CNS cellular differentiation. We have identified a cDNA corresponding to a new member of the POU/homeobox gene family. Expression of RNA encoded by this new gene occurs predominantly in the CNS. Thus, this new gene was designated Cns- 1. Cns-1 transcripts are expressed in differentiating cells cultured from the early postnatal cerebellum. Treatment of these cultured cells with NMDA results in an increase in the level of Cns-1 RNA. This increase is blocked by simultaneous treatment with the specific NMDA receptor antagonist amino-5-phosphonovaleric acid. Continued activation of the NMDA receptor allows maintenance of this new steady state level of Cns-1 mRNA for at least 5 d in these cultured cells. A transcription runoff assay suggests that this increase in the level of RNA is due, at least in part, to an increase in transcription from the Cns-1 gene. The NMDA-induced increase in Cns-1 mRNA was reduced by pretreatment with calcium chelators EGTA or 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′- tetraacetic acid (BAPTA) tetrakis(acetoxymethyl). These studies suggest that specific activation of the NMDA receptor in cultures of differentiating cerebellar cells increases Cns-1 gene expression and that calcium entry through the NMDA channel may be required for this response. This change in Cns-1 expression may modify phenotypic characteristics of these cultured cells.

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Stimulation of the receptor has a trophic effect on differentiating cerebellar granule cells

Cited by 216 publications

References 21 publications

Basic FGF regulates the expression of a functional 71 kDa NMDA receptor protein that mediates calcium influx and neurotoxicity in hippocampal neurons

Basic FGF regulates the expression of a functional 71 kDa NMDA receptor protein that mediates calcium influx and neurotoxicity in hippocampal neurons

Biphasic Coupling of Neuronal Nitric Oxide Synthase Phosphorylation to the NMDA Receptor Regulates AMPA Receptor Trafficking and Neuronal Cell Death

NMDA receptor activation in differentiating cerebellar cell cultures regulates the expression of a new POU gene, Cns-1

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