RGD Reference Report - H-Ras modulates N-methyl-D-aspartate receptor function via inhibition of Src tyrosine kinase activity. - Rat Genome Database

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

Authors: Thornton, C  Yaka, R  Dinh, S  Ron, D 
Citation: Thornton C, etal., J Biol Chem. 2003 Jun 27;278(26):23823-9. Epub 2003 Apr 14.
RGD ID: 11041007
Pubmed: PMID:12695509   (View Abstract at PubMed)
PMCID: PMC1196389   (View Article at PubMed Central)
DOI: DOI:10.1074/jbc.M302389200   (Journal Full-text)

Tyrosine phosphorylation of the NR2A and NR2B subunits of the N-methyl-d-aspartate (NMDA) receptor by Src protein-tyrosine kinases modulates receptor channel activity and is necessary for the induction of long term potentiation (LTP). Deletion of H-Ras increases both NR2 tyrosine phosphorylation and NMDA receptor-mediated hippocampal LTP. Here we investigated whether H-Ras regulates phosphorylation and function of the NMDA receptor via Src family protein-tyrosine kinases. We identified Src as a novel H-Ras binding partner. H-Ras bound to Src but not Fyn both in vitro and in brain via the Src kinase domain. Cotransfection of H-Ras and Src inhibited Src activity and decreased NR2A tyrosine phosphorylation. Treatment of rat brain slices with Tat-H-Ras depleted NR2A from the synaptic membrane, decreased endogenous Src activity and NR2A phosphorylation, and decreased the magnitude of hippocampal LTP. No change was observed for NR2B. We suggest that H-Ras negatively regulates Src phosphorylation of NR2A and retention of NR2A into the synaptic membrane leading to inhibition of NMDA receptor function. This mechanism is specific for Src and NR2A and has implications for studies in which regulation of NMDA receptor-mediated LTP is important, such as synaptic plasticity, learning, and memory and addiction.

Objects referenced in this article
Gene Hras HRas proto-oncogene, GTPase Rattus norvegicus
Gene Src SRC proto-oncogene, non-receptor tyrosine kinase Rattus norvegicus

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