Endocytosis and Degradative Sorting of NMDA Receptors by Conserved Membrane-Proximal Signals

Scott, Derek B.; Michailidis, Ioannis E.; Mu, Yuanyue; Logothetis, Diomedes E.; Ehlers, Michael

doi:10.1523/jneurosci.0780-04.2004

Cited by 113 publications

(107 citation statements)

References 76 publications

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“…Calpain cleavage of the NR2B C terminus would be expected to accelerate receptor loss from the surface by unmasking an AP2 binding site that promotes NR2B endocytosis and trafficking to late endosomes for degradation (Scott et al, 2004). We hypothesized that loss of NMDARs from the surface of YAC128 MSNs would be enhanced as a result of calpain cleavage, and that this might explain the similar NMDAR current densities observed in YAC128 and WT MSNs while YAC72 MSNs exhibit enhanced NMDAR surface expression and current (Fan et al, 2007).…”

Section: Accelerated Loss Of Surface Nr2b Mediated By Calpain Activitmentioning

confidence: 99%

“…Increased levels of calpain-cleaved NR2B would be expected to enhance NMDAR endocytosis and lysosomal degradation (Scott et al, 2004). Although NR2B expression levels are similar for WT and YAC72 striatal tissue from 2-month-old mice , NR2B expression has not been assessed in brains from YAC128 mice.…”

Section: Nr2b Levels Are Decreased In Yac128 Striatummentioning

confidence: 99%

“…Others have shown that NR2B is cleaved by calpain near the C terminus, removing the region where anchoring protein interactions take place, as well as the Tyr-1472 site which when phosphorylated promotes stability of receptors at the surface, and exposing the 843 Tyr-Trp-Gln-Phe sequence which promotes receptor internalization and subsequent degradation (Kornau et al, 1995;Ehlers et al, 1996;Roche et al, 2001;Scott et al, 2004;Dong et al, 2004). NMDARs with calpain-truncated NR2B initially remain functional and at the plasma membrane, but then are believed to be internalized and degraded rather than recycled (Simpkins et al, 2003;Dong et al, 2004).…”

Section: Role Of Calpain In Regulating Nmdar Surface Expressionmentioning

confidence: 99%

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Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

Cowan¹,

Fan²,

Fan³

et al. 2008

J. Neurosci.

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Huntington disease (HD), caused by CAG expansion in the ubiquitously expressed huntingtin gene, is characterized by early dysfunction and death of striatal medium-sized spiny neurons (MSNs). Previous work has shown MSN-specific alterations in NMDA receptor (NMDAR) expression and cell death signaling. Furthermore, studies in HD human brain tissue and a knock-in mouse model demonstrate increases in calpain activity, which can be stimulated by NMDARs and contribute to excitotoxicity. Here, we report increased calpain activity in MSNs from the yeast artificial chromosome (YAC) transgenic mouse model of HD, expressing human full-length huntingtin with 128 polyglutamine repeats (YAC128), compared with wild type. Moreover, the calpain-cleaved product of NMDAR subunit NR2B is increased early, and NR2B expression levels are reduced, in YAC128 striatum. Although steady-state NMDAR surface expression is similar in wild-type and YAC128 MSNs, the rate of loss of NR2B-containing surface receptors is enhanced in YAC128 MSNs, suggesting that NMDAR forward trafficking to the surface is also faster, as previously reported for YAC72 MSNs. Calpain inhibitor-1 treatment normalized the loss rate of surface NMDARs in YAC128 MSNs to that of wild type, and significantly increased surface NMDAR expression in YAC128, but not in wild type or YAC72. With acute NMDAR overstimulation, the increase in calpain activity correlated with polyglutamine length, and calpain inhibitor treatment reduced NMDA-induced apoptosis in YAC72 and YAC128 MSNs to wild-type levels. Thus, the cumulative effect of increasing huntingtin polyglutamine length is to enhance MSN sensitivity to excitotoxicity at least in part by calpain-mediated cell death signaling.

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Section: Accelerated Loss Of Surface Nr2b Mediated By Calpain Activitmentioning

confidence: 99%

Section: Nr2b Levels Are Decreased In Yac128 Striatummentioning

confidence: 99%

Section: Role Of Calpain In Regulating Nmdar Surface Expressionmentioning

confidence: 99%

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Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

Cowan¹,

Fan²,

Fan³

et al. 2008

J. Neurosci.

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“…Substantial evidence also supports a role for exocytic and endocytic receptor cycling in controlling AMPAtype glutamate receptor abundance at synapses during synaptic plasticity, but NMDARs have conventionally been thought to be stably fixed within the postsynaptic density (PSD). Challenging this view, recent studies have revealed that NMDARs can move rapidly in and out of the neuronal surface [14][15][16][17][18][19][20] . Atleast some forms of NMDAR exocytic and endocytic trafficking require synaptic activity 21 or ligand binding 17,22 ,23 , and may initiate synaptic changes that lead to synapse stabilization or elimination during development 16,23 . Despite recent progress, our knowledge of how postsynaptic NMDARs are linked to and regulated by the endocytic machinery is only just emerging.…”

mentioning

confidence: 99%

Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1

et al. 2006

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A key step in glutamatergic synapse maturation is the replacement of developmentally expressed N-methyl-D-aspartate receptors (NMDARs) with mature forms that differ in subunit composition, electrophysiological properties and propensity to elicit synaptic plasticity. However, the mechanisms underlying the removal and replacement of synaptic NMDARs are poorly understood. Here we demonstrate that NMDARs containing the developmentally regulated NR3A subunit undergo rapid endocytosis from the dendritic plasma membrane in cultured rat hippocampal neurons. This endocytic removal is regulated by PACSIN1/syndapin1, which directly and selectively binds the carboxy-terminal domain of NR3A through its NPF motifs and assembles a complex of proteins including dynamin and clathrin. Endocytosis of NR3A by PACSIN1 is activity dependent, and disruption of PACSIN1 function causes NR3A accumulation at synaptic sites. Our results reveal a new activity-dependent mechanism involved in the regulation of NMDAR expression at synapses during development, and identify a brain-specific endocytic adaptor that confers spatiotemporal and subunit specificity to NMDAR endocytosis.Stabilization and maturation of synapses is central to neural circuit formation. During development, excitatory synapses in the central nervous system are remodeled in response to

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“…The C0 domain contains two endocytic signals, tyrosine-based YKRH and lysine-based VWRK, which contribute to the endocytosis of NMDARs independent of NR2 subunits (Scott et al, 2004). The C0 domain also serves as a docking site for activated CaMKII (Leonard et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit

Zhang

Liang

et al. 2010

J. Neurosci.

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Glutamate-induced excitotoxicity has been implicated in the etiology of stroke, epilepsy, and neurodegenerative diseases. NMDA receptors (NMDARs) play a pivotal role in excitotoxic injury; however, clinical trials testing NMDAR antagonists as neuroprotectants have been discouraging. The development of novel neuroprotectant molecules is being vigorously pursued. Here, we report that downstream regulatory element antagonist modulator (DREAM) significantly inhibits surface expression of NMDARs and NMDAR-mediated current. Overexpression of DREAM showed neuroprotection against excitotoxic neuronal injury, whereas knockdown of DREAM enhanced NMDA-induced toxicity. DREAM could directly bind to the C0 domain of the NR1 subunit. Although DREAM contains multiple binding sites for the NR1 subunit, residues 21-40 of the N terminus are the main binding site for the NR1 subunit. Thus, 21-40 residues might relieve the autoinhibition conferred by residues 1-50 and derepress the DREAM core domain by a competitive mechanism. Intriguingly, the cell-permeable TAT-21-40 peptide, constructed according to the critical binding site of DREAM to the NR1 subunit, inhibits NMDARmediated currents in primary cultured hippocampal neurons and has a neuroprotective effect on in vitro neuronal excitotoxic injury and in vivo ischemic brain damage. Moreover, both pretreatment and posttreatment of TAT-21-40 is effective against excitotoxicity. In summary, this work reveals a novel, negative regulator of NMDARs and provides an attractive candidate for the treatment of excitotoxicity-related disease.

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Endocytosis and Degradative Sorting of NMDA Receptors by Conserved Membrane-Proximal Signals

Cited by 113 publications

References 76 publications

Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

Polyglutamine-Modulated Striatal Calpain Activity in YAC Transgenic Huntington Disease Mouse Model: Impact on NMDA Receptor Function and Toxicity

Endocytosis and synaptic removal of NR3A-containing NMDA receptors by PACSIN1/syndapin1

The DREAM Protein Negatively Regulates the NMDA Receptor through Interaction with the NR1 Subunit

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