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H-Ras modulates N-methyl-D-aspartate receptor function via inhibition of Src tyrosine kinase activity

Claire Thornton1, Rami Yaka, Son Dinh

  • 1Ernest Gallo Clinic and Research Center, University of California San Francisco, San Francisco, California 94110-3518, USA.

The Journal of Biological Chemistry
|April 16, 2003
PubMed

Insights

H-Ras negatively regulates NMDA receptor function by inhibiting Src-mediated phosphorylation of NR2A. This finding impacts understanding of synaptic plasticity, learning, memory, and addiction.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cellular Signaling

Background:

  • Tyrosine phosphorylation of NMDA receptor subunits (NR2A/NR2B) by Src kinases regulates channel activity and long-term potentiation (LTP).
  • H-Ras deletion enhances NR2 tyrosine phosphorylation and hippocampal LTP, suggesting a regulatory role.

Purpose of the Study:

  • To investigate if H-Ras modulates NMDA receptor phosphorylation and function through Src family kinases.
  • To identify the specific interaction between H-Ras and Src family kinases.

Main Methods:

  • Investigated H-Ras binding partners using in vitro and in vivo brain assays.
  • Examined the effect of H-Ras and Src co-transfection on Src activity and NR2A phosphorylation.
  • Utilized Tat-H-Ras treatment on rat brain slices to assess NR2A localization, Src activity, NR2A phosphorylation, and hippocampal LTP.

Main Results:

  • Src was identified as a novel H-Ras binding partner, interacting via the Src kinase domain.
  • H-Ras/Src co-transfection inhibited Src activity and reduced NR2A tyrosine phosphorylation.
  • Tat-H-Ras treatment decreased NR2A synaptic membrane levels, reduced Src activity and NR2A phosphorylation, and diminished hippocampal LTP magnitude, with no effect on NR2B.

Conclusions:

  • H-Ras negatively regulates Src-mediated phosphorylation of NR2A and its synaptic membrane retention, thereby inhibiting NMDA receptor function.
  • This mechanism is specific to Src and NR2A, offering insights into synaptic plasticity, learning, memory, and addiction.

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