The Postsynaptic Density Protein PSD‐95 Differentially Regulates Insulin‐ and Src‐Mediated Current Modulation of Mouse NMDA Receptors Expressed in <i>Xenopus</i> Oocytes

Liao, Guey Ying; Kreitzer, Matthew A.; Sweetman, Brian J.; Leonard, John P.

doi:10.1046/j.1471-4159.2000.0750282.x

Cited by 46 publications

(36 citation statements)

References 28 publications

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“…These findings demonstrate that kinase-dependent phosphorylation regulates interaction of synaptic scaffolding proteins with NMDARs. Conversely, PSD-95 attenuates PKC potentiation of NMDARs expressed as the ratio of potentiated to control responses (26)(27)(28). However, the molecular mechanisms by which synaptic scaffolding proteins modulate kinase effects on NMDAR gating and trafficking are not well delineated.…”

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confidence: 99%

PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating

Lin

Jover‐Mengual

Wong

et al. 2006

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

104

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Neuronal NMDA receptors (NMDARs) colocalize with postsynaptic density protein-95 (PSD-95), a putative NMDAR anchoring protein and core component of the PSD, at excitatory synapses. PKC activation and PSD-95 expression each enhance NMDAR channel opening rate and number of functional channels at the cell surface. Here we show in Xenopus oocytes that PSD-95 and PKC potentiate NMDA gating and trafficking in a nonadditive manner. PSD-95 and PKC each enhance NMDA channel activity, with no change in single-channel conductance, reversal potential or mean open time. PSD-95 and PKC each potentiate NMDA channel opening rate ( k β ) and number of functional channels at the cell surface (N), as indicated by more rapid current decay and enhanced charge transfer in the presence of the open channel blocker MK-801. PSD-95 and PKC each increase NMDAR surface expression, as indicated by immunofluorescence. PKC potentiates NMDA channel function and NMDAR surface expression to the same final absolute values in the absence or presence of PSD-95. Thus, PSD-95 partially occludes PKC potentiation. We further show that Ser-1462, a putative phosphorylation target within the PDZ-binding motif of the NR2A subunit, is required for PSD-95-induced potentiation and partial occlusion of PKC potentiation. Coimmunoprecipitation experiments with cortical neurons in culture indicate that PKC activation promotes assembly of NR2 with NR1, and that the newly assembled NMDARs are not associated with PSD-95. These findings predict that synaptic scaffolding proteins and protein kinases convergently modulate NMDAR gating and trafficking at synaptic sites.

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mentioning

confidence: 99%

PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating

Lin

Jover‐Mengual

Wong

et al. 2006

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

104

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“…One of the very important scaffolding proteins known to interact with NMDAR is PSD-95 (Kornau et al 1995;Niethammer et al 1996;Liao et al 2000;Roy et al 2002;Rutter et al 2002;Lavezzari et al 2003). Recently, it has been reported that PSD-95 interacts with GlyT1 and impairs its internalization (Cubelos et al 2005).…”

Section: Discussionmentioning

confidence: 99%

Sustained saturating level of glycine induces changes in NR2B‐containing‐NMDA receptor localization in the CA1 region of the hippocampus

Imamura

Pabba

et al. 2008

Journal of Neurochemistry

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1Both authors contributed equally to the manuscript.Abbreviations used: ACSF, artificial cerebrospinal fluid; AMPAR, aamino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor; EPSC, excitatory post-synaptic current; GlyT1, glycine transporter type 1; GlyT1+/), heterozygote mice for GlyT1 gene; NMDARs, N-methyl-Daspartate glutamatergic receptors; TBS, Tris-buffered saline. AbstractPost-synaptic actions of glycine are terminated by specialized transporters. There are two genes encoding glycine transporters, GlyT1 and GlyT2. Glycine acts as a co-agonist at N-methyl-D-aspartate glutamatergic receptors (NMDARs). Blockage of GlyT1 enhances NMDAR function by controlling ambient glycine concentrations. Using whole-cell patch-clamp recordings of acute hippocampal slices, we investigated NMDAR kinetics of CA1 pyramidal neurons of mice expressing 50% of GlyT1 (GlyT1+/)). In this study, we report that the glycine modulatory site of the NMDAR at CA1 synapses is saturated in GlyT1+/) but not in wild-type (WT) mice. We also found that the effect of ifenprodil, a highly selective NR2B-containing-NMDAR antagonist, is significantly reduced at CA1 synapses in GlyT1+/) compared to WT mice while immunoblotting experiments do not show significant differences for NR1, NR2A-B-C-D subunits in both types of mice, suggesting alteration in NR2B-containing-NMDAR localization under a state of chronic saturating level of endogenous glycine. Using a pharmacological approach with MK-801 and DL-TBOA, we discriminated synaptic vis-à-vis extra-synaptic NMDARs. We found that NR2B-containing-NMDARs are expressed at a higher level in the extra-synaptic area of CA1 pyramidal neurons from GlyT1+/) compared to WT mice. Our results demonstrate that chronic saturating level of glycine induces significant changes in NMDAR localization and kinetic. Therefore, results from our study should help to gain a better understanding of the role of glycine in pathological conditions.

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“…Recent findings suggest that the 95 kDa postsynpatic density protein, PSD-95, acts as a scaffolding for associating NMDA receptors and protein kinases (Tezuka et al 1999), and PSD-95 appears to play a role in controlling kinase modulation of NMDA receptor currents (Liao et al 2000). Further, A-kinase anchoring proteins (AKAPs) such as AKAP79/150 provide a scaffold for signaling enzymes, PKA and PKC (Klauck et al 1996).…”

Section: Introductionmentioning

confidence: 99%