Characterization of Fyn-mediated Tyrosine Phosphorylation Sites on GluRε2 (NR2B) Subunit of the N-Methyl-d-aspartate Receptor

Nakazawa, Takahiro; Komai, Shoji; Tezuka, T.; Hisatsune, Chihiro; Umemori, Hisashi; Semba, Kentaro; Mishina, Masayoshi; Manabe, Toshiya; Yamamoto, Tadashi

doi:10.1074/jbc.m008085200

Cited by 433 publications

(472 citation statements)

References 57 publications

(61 reference statements)

Supporting

Mentioning

460

Contrasting

Unclassified

Order By: Relevance

“…Purification of GST-Src (WT or K298M) and in vitro kinase reaction were performed as described (Nakazawa et al, 2001). 293T cells that express FLAG-Cbl-c WT or mutants were lysed in TNE buffer and the cleared lysates were incubated with in vitro phosphorylated GST-Src (1 mg) at 41C for 4 h. For peptide-inhibition experiments, a synthetic phospho-or nonphosphorylated peptide that was derived from Src was added during incubation.…”

Section: In Vitro Binding Assaymentioning

confidence: 99%

Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

et al. 2003

Self Cite

View full text Add to dashboard Cite

Section: In Vitro Binding Assaymentioning

confidence: 99%

Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

et al. 2003

Self Cite

View full text Add to dashboard Cite

“…The phosphorylation level of NR2B increased markedly during EW in wild-type mice (P Ͻ 0.05; Fig. 4) but remained unaffected in tPAϪ͞Ϫ mice, suggesting that tPA-mediated changes permit the activation of NR2B-containing receptors by intracellular kinases (38). However, the contribution of activity-independent constitutive phosphorylation of NR2B receptors remains to be determined.…”

Section: Results Tpa Is Up-regulated By Ethanol and Ewmentioning

confidence: 96%

“…To investigate how NR2B is regulated by tPA, we examined phosphorylation of NR2B at Tyr-1472, a site that is involved in modulating the properties of the NR1͞NR2B receptor channel, and synaptic plasticity (38). The phosphorylation level of NR2B increased markedly during EW in wild-type mice (P Ͻ 0.05; Fig.…”

Section: Results Tpa Is Up-regulated By Ethanol and Ewmentioning

confidence: 99%

Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors

Pawlak

Melchor²,

Matys³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

129

134

View full text Add to dashboard Cite

Chronic ethanol abuse causes up-regulation of NMDA receptors, which underlies seizures and brain damage upon ethanol withdrawal (EW). Here we show that tissue-plasminogen activator (tPA), a protease implicated in neuronal plasticity and seizures, is induced in the limbic system by chronic ethanol consumption, temporally coinciding with up-regulation of NMDA receptors. tPA interacts with NR2B-containing NMDA receptors and is required for up-regulation of the NR2B subunit in response to ethanol. As a consequence, tPA-deficient mice have reduced NR2B, extracellular signal-regulated kinase 1͞2 phosphorylation, and seizures after EW. tPA-mediated facilitation of EW seizures is abolished by NR2B-specific NMDA antagonist ifenprodil. These results indicate that tPA mediates the development of physical dependence on ethanol by regulating NR2B-containing NMDA receptors.proteases ͉ excitotoxicity ͉ alcoholism

show abstract

“…To further examine the role of STEP in ethanol's inhibitory action, we measured the effect of ethanol on tyrosine phosphorylation of the NMDAR in the STEP KO mice, because the NMDAR activity is regulated by protein phosphorylation (36). Recent work has shown that the functional expression of NMDARs is regulated by phosphorylation of NR2B Tyr 1472 .…”

Section: Discussionmentioning

confidence: 99%

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Hicklin¹,

Radcliffe

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Alcohol's deleterious effects on memory are well known. Acute alcohol-induced memory loss is thought to occur via inhibition of NMDA receptor (NMDAR)-dependent long-term potentiation in the hippocampus. We reported previously that ethanol inhibition of NMDAR function and long-term potentiation is correlated with a reduction in the phosphorylation of Tyr 1472 on the NR2B subunit and ethanol's inhibition of the NMDAR field excitatory postsynaptic potential was attenuated by a broad spectrum tyrosine phosphatase inhibitor. These data suggested that ethanol's inhibitory effect may involve protein tyrosine phosphatases. Here we demonstrate that the loss of striatal-enriched protein tyrosine phosphatase (STEP) renders NMDAR function, phosphorylation, and long-term potentiation, as well as fear conditioning, less sensitive to ethanol inhibition. Moreover, the ethanol inhibition was "rescued" when the active STEP protein was reintroduced into the cells. Taken together, our data suggest that STEP contributes to ethanol inhibition of NMDAR function via dephosphorylation of tyrosine sites on NR2B receptors and lend support to the hypothesis that STEP may be required for ethanol's amnesic effects.whole-cell currents | null mutant mice A lcohol-induced memory deficits have been well documented in humans, as well as animal studies (1). Long-term potentiation (LTP) is widely accepted as a cellular mechanism underlying learning and memory in the hippocampus, as well as other brain regions (2), and is dependent upon NMDA receptor (NMDAR) activation (3). Acute ethanol application in adult rodents inhibits NMDAR channel activity (4, 5). Ethanol's inhibitory effect on NMDARs is widely thought to underlie both the blockade of LTP and the acute amnesic effects of ethanol. Moreover, recent work suggests that ethanol's effect on the NMDAR may play a role in the addictive nature of ethanol (6, 7).NMDARs in the hippocampus consist of mainly NR1/NR2A, NR1/NR2B, and NR1/NR2A/NR2B receptor-subunit complexes (8). Although NR1 subunits are required to form an active ion channel, incorporation of the various NR2 subunits regulate NMDAR channel activity by altering the channel kinetics and mediating the differential effects of pharmacological agents, including alcohol (9-11). It has previously been shown that activation of members of the Src-family of kinases (SFKs) enhances NMDAR currents (12). Previous studies have demonstrated a correlation between ethanol inhibition of NMDAR function and dephosphorylation of tyrosine residues on the NR2A and NR2B subunits (13). In particular, ethanol was found to reduce the phosphorylation of a site on the NR2B subunit Tyr 1472 that has been shown to regulate endocytosis and function of NMDARs (14,15). Inhibition of protein tyrosine phosphatase activity using a nonspecific inhibitor, bpV(phen), significantly reduced ethanol inhibition of NMDAR field excitatory postsynaptic potentials (fEPSPs), suggesting that ethanol may inhibit NMDARs via activation of a tyrosine phosphatase (13). FerraniKile et al. indepe...

show abstract

Characterization of Fyn-mediated Tyrosine Phosphorylation Sites on GluRε2 (NR2B) Subunit of the N-Methyl-d-aspartate Receptor

Cited by 433 publications

References 57 publications

Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

Cbl-c suppresses v-Src-induced transformation through ubiquitin-dependent protein degradation

Ethanol-withdrawal seizures are controlled by tissue plasminogen activator via modulation of NR2B-containing NMDA receptors

Alcohol inhibition of the NMDA receptor function, long-term potentiation, and fear learning requires striatal-enriched protein tyrosine phosphatase

Contact Info

Product

Resources

About