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

Mark P. Mattson, Keshava N. Kumar, Hong Wang, Bin Cheng, Elias K. Michaelis

Research output: Contribution to journalArticlepeer-review

Abstract

Basic fibroblast growth factor (bFGF) was recently found to modulate the outgrowth-regulating effects of glutamate, and protected neurons from several brain regions against excitotoxic/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.

Original languageEnglish (US)
Pages (from-to)4575-4588
Number of pages14
JournalJournal of Neuroscience
Volume13
Issue number11
StatePublished - 1993
Externally publishedYes

Keywords

  • Antisense oligonucleotide
  • Calcium
  • Excitotoxicity
  • Fura-2
  • Growth factors
  • mRNA
  • Neuronal death
  • NMDA

ASJC Scopus subject areas

  • Neuroscience(all)

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