Disease relevance of Dlgh4

• Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia [1].
• These results suggest that the PSD-95 family proteins and S-SCAM have a novel function as KIF1Balpha receptors, linking KIF1Balpha to its specific cargos, and are involved in peripheral neuropathies [2].
• The coimmunoprecipitation of SynGAP with PSD-95 decreased after ischemia [3].
• Cholesterol repletion counteracted the ability of methylated beta-CD to protect against NMDA toxicity, and reversed NR2B, PSD-95 and nNOS localization to Triton X-100 insoluble membrane fraction [4].
• We investigated the effects of transient cerebral ischemia on protein interactions involving PSD-95 and the NMDA receptor in the rat hippocampus [5].

High impact information on Dlgh4

• Here, we identify palmitate cycling on PSD-95 at the synapse and find that palmitate turnover on PSD-95 is regulated by glutamate receptor activity [6].
• In a nonneuronal model system, clustering of PSD-95, stargazin, and AMPA receptors is also regulated by ongoing palmitoylation of PSD-95 at the plasma membrane [6].
• Synaptic strength regulated by palmitate cycling on PSD-95 [6].
• The palmitoylated postsynaptic density protein, PSD-95, regulates synaptic plasticity and associates with the AMPA receptor trafficking protein, stargazin [6].
• Postsynaptic expression of PSD-95 also enhanced maturation of the presynaptic terminal [7].

Chemical compound and disease context of Dlgh4

• PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus [8].
• Ischemia followed by reperfusion resulted in a decrease in the solubility of the NMDA receptor and PSD-95 in 1% sodium deoxycholate, the decrease being greater in the vulnerable CA1 hippocampal subfield than in the less sensitive CA3/dentate gyrus regions [5].
• Solubilization of the kainic acid receptor GluR6/7 and the PSD-95 binding proteins, neuronal nitric oxide synthase and p135synGAP, also decreased following ischemia [5].
• Increased tyrosine phosphorylation of alpha(1C) subunits of L-type voltage-gated calcium channels and interactions among Src/Fyn, PSD-95 and alpha(1C) in rat hippocampus after transient brain ischemia [9].
• Furthermore, following dopamine-depletion and development of behavioral deficits in Rotorod performance, indicative of parkinsonism, we observed a dramatic decrease in total striatal levels of PSD-95 and SAP97 (to 25.6 +/- 9.9% and 19.0 +/- 5.0% of control, respectively) [10].

Biological context of Dlgh4

• Members of the PSD-95 family might serve to anchor NMDA receptors to the submembrane cytoskeleton and aid in the assembly of signal transduction complexes at postsynaptic sites [11].
• However, the precise functional role played by PSD-95 in regulating synaptic transmission and plasticity remains undefined [12].
• Transfection of PSD-95 was further accompanied by an increase in the frequency, but not amplitude, of AMPAR-mediated mEPSCs [12].
• Modulation of dopamine mediated phosphorylation of AMPA receptors by PSD-95 and AKAP79/150 [13].
• A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis [14].

Anatomical context of Dlgh4

• In addition, cAMP facilitated trafficking of TrkB to dendritic spines, possibly by promoting its interaction with synaptic scaffolding protein PSD-95 [15].
• We provide evidence of an activity-dependent redistribution of PSD-95 to dendrites in central visual neurons that is tied to eye opening [16].
• The effects of MALS-2 and PSD-95 on the channel activity of NMDA receptors were compared using the Xenopus oocyte expression system [17].
• PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex [12].
• Expression of PSD95 in the rat sciatic nerve [18].

Associations of Dlgh4 with chemical compounds

• Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases [11].
• Interactions between Src family protein tyrosine kinases and PSD-95 [19].
• The second PDZ domain in PSD-95 binds to the seven-amino acid, COOH-terminal domain containing the terminal tSXV motif (where S is serine, X is any amino acid, and V is valine) common to NR2 subunits and certain NR1 splice forms [20].
• In hippocampal slice cultures, the expression of PSD-95-green fluorescent protein (PSD-95-GFP) increases AMPAR currents by selectively delivering glutamate receptor 1 (GluR1)-containing receptors to synapses, thus mimicking long-term potentiation (LTP) [21].
• Metabolic labeling of brain slices or cultured cells demonstrates that PSD-95 is modified by thioester-linked palmitate, a long chain fatty acid that targets proteins to cell membranes [22].

Physical interactions of Dlgh4

• Neuroligin also interacts with SAP90/PSD95, a multidomain scaffolding protein thought to recruit proteins to postsynaptic sites [23].
• These data indicate that postsynaptic targeting of neuroligin does not rely on the scaffolding action of SAP90/PSD95 and is not induced by binding to presynaptic neurexin [23].
• Deleting the PSD-95 binding motif of Kv1.4 eliminated this recruitment, as did substituting a palmitoylation-deficient PSD-95 mutant [24].
• Both alphaCaMKII and PSD-95 have been shown previously to bind NR2 subunits of the NMDA receptor complex [25].
• The binding site of the active components in the extract overlapped with the nNOS/NR2B-binding pocket of PDZ2 of PSD-95 [26].

Co-localisations of Dlgh4

• The majority of NMDA receptor clusters were colocalized with the postsynaptic density proteins PSD-95, PSD-93, and SAP 102 [27].
• Immunocytochemical localization of myosin-Va in cultured hippocampal neurons shows that it partially colocalizes with PSD-95 at synapses and is also diffusely localized in cell bodies, dendrites, and axons [28].

Regulatory relationships of Dlgh4

• Together our results suggest that PSD-95 may be important for localizing and/or regulating multiple Src protein tyrosine kinases at the NMDA receptor multiprotein complex [19].
• N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4 [22].
• In addition, Ser/Ala1289 and Ser/Asp1289 point mutations on the unique CaMKII phosphosite of NR2A did not significantly influence the binding of native alphaCaMKII and PSD-95 to the NR2A C-tail [25].
• Taken together, these findings suggest that activation of the PI3K-Akt-mTOR signaling pathway is essential for the insulin-induced up-regulation of local PSD-95 protein synthesis in neuronal dendrites and indicate a new molecular mechanism that may contribute to the modulation of synaptic function by insulin in hippocampal area CA1 [29].
• The present findings suggest that each isoform of the PSD-95 binding protein is differentially expressed in a development-dependent manner and may be involved in the complex formation of PSD-95 and channel/receptors at the postsynaptic density [30].

Other interactions of Dlgh4

• The PSD-95/Dlg/ZO-1 (PDZ) domain-containing proteins MALS and PSD-95 localize to post-synaptic densities and bind the COOH-termini of NR2 subunits of the NMDA receptor [17].
• These data suggested that PSD-95 is critical for facilitating NR2A tyrosine phosphorylation by Src family kinases in postischemic brain [31].
• The same mutation impaired the functional ability of PSD-95 to cluster Kv1.4 potassium channels in heterologous cells [32].
• Following neurotransmitter stimulation, PSD-95 levels are negatively correlated with the magnitude of internalized GluR1 in individual neurons [14].
• To further illustrate the mechanisms underlying these processes, we examined the effects of transient (15 min) brain ischemia followed by reperfusion (0, 30 min, 6 h, 1, 3 days) on serine phosphorylation of SynGAP and interactions involving SynGAP, postsynaptic density protein 95 (PSD95) and CaMKII in rat hippocampus [8].

Analytical, diagnostic and therapeutic context of Dlgh4

• The 15-min reperfusion after brain ischemia induced enhanced co-immunoprecipitation of PSD95, Fyn and NR2A with one another [1].
• The associations of PSD95 with Fyn and NR2A increased at 0-24 h, 0-1 h of reperfusion, up to 6.9- and 2.1-fold relative to sham groups, respectively [1].
• Furthermore, the full-length beta(1)AR associates with PSD-95 in cells, as determined by co-immunoprecipitation experiments and immunofluorescence co-localization studies [33].
• However, the membrane-permeable peptide disrupted the NMDA receptor-PSD-95 interaction in slices as tested by immunoprecipitation and subsequent immunoblotting [34].
• We got an interesting result that the rat sciatic nerve obviously showed PSD95 immunoreactivity especially in the nodal and paranodal regions, and we also identified a distinct band of PSD95 by western blot [18].

References