Differential interaction of NMDA receptor subtypes with the post‐synaptic density‐95 family of membrane associated guanylate kinase proteins

Cousins, Sarah L.; Papadakis, Michalis; Rutter, A. Richard; Stephenson, F. Anne

doi:10.1111/j.1471-4159.2007.05067.x

Cited by 56 publications

(54 citation statements)

References 45 publications

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“…Furthermore, we used a heterologous cell system to further determine the impact of the ligand on the interaction between NR2 subunit and the most abundant PDZ proteins, PSD-95. In heterologous cells, 2A-and 2B-NMDARs coimmunoprecipitate with the four PSD-95 MAGUK family of scaffolding proteins (34). In addition, PSD-95 enhances 2A-and 2B-NMDAR cell surface expression through a process that requires the NR2 C terminus sequence -ESDV (34 (Fig.…”

Section: Interaction Between Nr2a Subunits and Psd-95 Is Specificallymentioning

confidence: 97%

Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins

Bard

Sainlos

Bouchet

et al. 2010

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

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The relative content of NR2 subunits in the NMDA receptor confers specific signaling properties and plasticity to synapses. However, the mechanisms that dynamically govern the retention of synaptic NMDARs, in particular 2A-NMDARs, remain poorly understood. Here, we investigate the dynamic interaction between NR2 C termini and proteins containing PSD-95/Discs-large/ZO-1 homology (PDZ) scaffold proteins at the single molecule level by using highresolution imaging. We report that a biomimetic divalent competing ligand, mimicking the last 15 amino acids of NR2A C terminus, specifically and efficiently disrupts the interaction between 2A-NMDARs, but not 2B-NMDARs, and PDZ proteins on the time scale of minutes. Furthermore, displacing 2A-NMDARs out of synapses lead to a compensatory increase in synaptic NR2B-NMDARs, providing functional evidence that the anchoring mechanism of 2A-or 2B-NMDARs is different. These data reveal an unexpected role of the NR2 subunit divalent arrangement in providing specific anchoring within synapses, highlighting the need to study such dynamic interactions in native conditions. lateral diffusion | glutamate receptor | trafficking | biomimetic multivalent ligand | development T he identification of the cellular mechanisms involved in the regulation of glutamate receptor trafficking is crucial to our understanding of synaptic maturation and plasticity. One common paradigm of these processes is the activation of the calciumpermeable postsynaptic NMDA receptors (NMDARs). In the neocortex, the most abundant types of NMDARs are composed of NR1 subunits associated with NR2A (enriched in synapses) and/or NR2B subunits (1). Rapid changes in the synaptic 2A/2B NMDAR ratio have been reported during connection refinements and synaptic plasticity (2), and several key molecular interactions have been shown to control the trafficking of intracellular and membrane NMDARs (3-6).The intracellular proteins that interact with the C terminus of the subunits, through direct binding or modification of the phosphorylation state, are likely candidates for regulating the synaptic retention of NMDARs. Indeed, intracellular domains of NR2 subunits provide a binding motif for proteins of the postsynaptic density such as PSD-95 and SAP102 (7-10). The binding of the NR2B subunit C terminus to PDZ domain-containing scaffold proteins regulates, in part, the synaptic retention of this receptor (8,9,(11)(12)(13)(14). For the 2A-NMDARs, which make up the majority of synaptic NMDARs, the role of such interactions in synaptic retention remains controversial. Indeed, long-term expression of NR2A subunits with a truncated or mutated C terminus does not affect synaptic NMDAR currents in cerebellar or hippocampal neurons (9, 15), whereas deletion of the NR2A subunit C terminus sequence significantly reduces NMDAR synaptic signaling (11,14,16,17). Currently, there is no simple explanation for this discrepancy, and the use of long-term expression of exogenous NR subunits and lack of good pharmacological tools to discriminate betwee...

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Section: Interaction Between Nr2a Subunits and Psd-95 Is Specificallymentioning

confidence: 97%

Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins

Bard

Sainlos

Bouchet

et al. 2010

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

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“…Dlg4 interacts with several other scaffolding proteins to serve as anchorages also for ionotropic AMPA-selective GluRs such as Gria2 [67]. Modifications of Dgl proteins function in the glutamatergic synapse, such as alterations of their interaction with NMDAR regulatory subunits, and are common events in several neurodegenerative disorders [68,69,70,71]. Decreased expression of NMDAR-associated proteins has been found in the frontal Cx of elderly patients with schizophrenia [72] while decreased levels of Dlg4 have been reported in the Hp from subjects with amnestic mild cognitive impairment [73] and in the inferior temporal Cx of AD subjects [74]; in contrast, a significant increase in Dlg4 protein in Brodmann's area 9 of AD patients suggests a brain-site-specific change in NMDAR trafficking and may represent a novel marker of functional significance for the disease [75].…”

Section: Discussionmentioning

confidence: 99%

Brain-Site-Specific Proteome Changes Induced by Neuronal P60TRP Expression

Manavalan

Mishra²,

Sze³

et al. 2013

Neurosignals

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p60 transcription regulator protein (p60TRP) facilitates the processing of the amyloid precursor protein towards the non-amyloidogenic pathway by inhibiting the β-secretase action. This protein was initially identified to be downregulated in the temporal lobe of brains from Alzheimer's disease patients. p60TRP is one of the G-protein-coupled receptor (GPCR)-associated proteins which directly influences the signalling capacity of GPCRs. In the present study, we investigated the brain-region-specific proteome profile of transgenic p60TRP mice to gain an insight into the molecular events mediated by the long-term effect of neuronal p60TRP overexpression on brain proteome changes and its potential implication for neuronal functions in the central nervous system. Using a proteomics research approach based on isobaric tags for relative and absolute quantitation, we identified 2,025 proteins, whereby 1,735 proteins were quantified, out of which 56 were found to be significantly altered in the cortex and/or hippocampus of neuronal transgenic neuronal p60TRP mice. Our data suggests that in vivo overexpression of neuronal p60TRP significantly affects cognitive and neuroprotective capacities.

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“…Although PSD-95 and SAP102 bind NR2 and htt through PDZ and SH3 domains, respectively, other regions of these MAGUKs likely affect the strength of this binding. Both PDZ1 and PDZ2 contribute to MAGUK interactions with NR2 subunits (Kornau et al, 1995), whereas regions upstream of the NR2 C-terminal PDZ ligand, which differ between NR2A and NR2B, contribute to interaction of these subunits with PSD-95 (Cousins et al, 2008) and may explain differences in strength of binding to various MAGUKs (Cui et al, 2007). Similarly, sequence differences around the SH3 domain of PSD-95 and SAP102 may contribute to differential interaction of these two MAGUKs with the polyproline of htt.…”

Section: Modulation Of Nmdar Surface Expression By Pdz Domain Interacmentioning

confidence: 99%

Interaction of Postsynaptic Density Protein-95 with NMDA Receptors Influences Excitotoxicity in the Yeast Artificial Chromosome Mouse Model of Huntington's Disease

Fan

Cowan²,

Zhang³

et al. 2009

J. Neurosci.

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Evidence suggests that NMDA-type glutamate receptors contribute to degeneration of striatal medium-sized spiny neurons (MSNs) in Huntington's disease (HD). Previously, we demonstrated that NMDA receptor (NMDAR)-mediated current and/or toxicity is increased in MSNs from the yeast artificial chromosome (YAC) transgenic mouse model expressing polyglutamine (polyQ)-expanded (mutant) full-length human huntingtin (htt). Others have shown that membrane-associated guanylate kinases (MAGUKs), such as PSD-95 and SAP102, modulate NMDAR surface expression and excitotoxicity in hippocampal and cortical neurons and that htt interacts with PSD-95. Here, we tested the hypothesis that an altered association between MAGUKs and NMDARs in mutant huntingtin-expressing cells contributes to increased susceptibility to excitotoxicity. We show that htt coimmunoprecipitated with SAP102 in HEK293T cells and striatal tissue from wild-type and YAC transgenic mice; however, the association of SAP102 with htt or the NMDAR NR2B subunit was unaffected by htt polyQ length, whereas association of PSD-95 with NR2B in striatal tissue was enhanced by increased htt polyQ length. Treatment of cultured MSNs with Tat-NR2B9c peptide blocked binding of NR2B with SAP102 and PSD-95 and reduced NMDAR surface expression by 20% in both YAC transgenic and wild-type MSNs, and also restored susceptibility to NMDAR excitoxicity in YAC HD MSNs to levels observed in wild-type MSNs; a similar effect on excitotoxicity was observed after knockdown of PSD-95 by small interfering RNA. Unlike previous findings in cortical and hippocampal neurons, rescue of NMDA toxicity by Tat-NR2B9c occurred independently of any effect on neuronal nitric oxide synthase activity. Our results elucidate further the mechanisms underlying enhanced excitotoxicity in HD.

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Differential interaction of NMDA receptor subtypes with the post‐synaptic density‐95 family of membrane associated guanylate kinase proteins

Cited by 56 publications

References 45 publications

Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins

Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins

Brain-Site-Specific Proteome Changes Induced by Neuronal P60TRP Expression

Interaction of Postsynaptic Density Protein-95 with NMDA Receptors Influences Excitotoxicity in the Yeast Artificial Chromosome Mouse Model of Huntington's Disease

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