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Gene Review

Dlg4  -  discs, large homolog 4 (Drosophila)

Rattus norvegicus

Synonyms: Disks large homolog 4, Dlgh4, PSD-95, PSD95, Postsynaptic density protein 95, ...
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Disease relevance of Dlgh4


High impact information on Dlgh4


Chemical compound and disease context of Dlgh4


Biological context of Dlgh4


Anatomical context of Dlgh4


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


  1. Activation of NMDA receptors and L-type voltage-gated calcium channels mediates enhanced formation of Fyn-PSD95-NR2A complex after transient brain ischemia. Hou, X.Y., Zhang, G.Y., Yan, J.Z., Chen, M., Liu, Y. Brain Res. (2002) [Pubmed]
  2. Association of the kinesin superfamily motor protein KIF1Balpha with postsynaptic density-95 (PSD-95), synapse-associated protein-97, and synaptic scaffolding molecule PSD-95/discs large/zona occludens-1 proteins. Mok, H., Shin, H., Kim, S., Lee, J.R., Yoon, J., Kim, E. J. Neurosci. (2002) [Pubmed]
  3. Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP. Pei, L., Teves, R.L., Wallace, M.C., Gurd, J.W. J. Cereb. Blood Flow Metab. (2001) [Pubmed]
  4. Protection by cholesterol-extracting cyclodextrins: a role for N-methyl-D-aspartate receptor redistribution. Abulrob, A., Tauskela, J.S., Mealing, G., Brunette, E., Faid, K., Stanimirovic, D. J. Neurochem. (2005) [Pubmed]
  5. Altered interaction between PSD-95 and the NMDA receptor following transient global ischemia. Takagi, N., Logan, R., Teves, L., Wallace, M.C., Gurd, J.W. J. Neurochem. (2000) [Pubmed]
  6. Synaptic strength regulated by palmitate cycling on PSD-95. El-Husseini, A.e.l.-.D., Schnell, E., Dakoji, S., Sweeney, N., Zhou, Q., Prange, O., Gauthier-Campbell, C., Aguilera-Moreno, A., Nicoll, R.A., Bredt, D.S. Cell (2002) [Pubmed]
  7. PSD-95 involvement in maturation of excitatory synapses. El-Husseini, A.E., Schnell, E., Chetkovich, D.M., Nicoll, R.A., Bredt, D.S. Science (2000) [Pubmed]
  8. PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus. Song, B., Yan, X.B., Zhang, G.Y. Brain Res. (2004) [Pubmed]
  9. 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. Hou, X.Y., Zhang, G.Y., Yan, J.Z., Liu, Y. Brain Res. (2003) [Pubmed]
  10. Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia. Nash, J.E., Johnston, T.H., Collingridge, G.L., Garner, C.C., Brotchie, J.M. FASEB J. (2005) [Pubmed]
  11. Interaction between the C terminus of NMDA receptor subunits and multiple members of the PSD-95 family of membrane-associated guanylate kinases. Niethammer, M., Kim, E., Sheng, M. J. Neurosci. (1996) [Pubmed]
  12. PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex. Béïque, J.C., Andrade, R. J. Physiol. (Lond.) (2003) [Pubmed]
  13. Modulation of dopamine mediated phosphorylation of AMPA receptors by PSD-95 and AKAP79/150. Swayze, R.D., Lisé, M.F., Levinson, J.N., Phillips, A., El-Husseini, A. Neuropharmacology (2004) [Pubmed]
  14. A proteasome-sensitive connection between PSD-95 and GluR1 endocytosis. Bingol, B., Schuman, E.M. Neuropharmacology (2004) [Pubmed]
  15. Cyclic AMP controls BDNF-induced TrkB phosphorylation and dendritic spine formation in mature hippocampal neurons. Ji, Y., Pang, P.T., Feng, L., Lu, B. Nat. Neurosci. (2005) [Pubmed]
  16. Eye opening induces a rapid dendritic localization of PSD-95 in central visual neurons. Yoshii, A., Sheng, M.H., Constantine-Paton, M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  17. Differential modulation of NR1-NR2A and NR1-NR2B subtypes of NMDA receptor by PDZ domain-containing proteins. Iwamoto, T., Yamada, Y., Hori, K., Watanabe, Y., Sobue, K., Inui, M. J. Neurochem. (2004) [Pubmed]
  18. Expression of PSD95 in the rat sciatic nerve. Yoo, H.J., Cho, I.H., Lee, J.H., Choe, N.H., Kang, T.Y., Chang, B.J. J. Vet. Sci. (2003) [Pubmed]
  19. Interactions between Src family protein tyrosine kinases and PSD-95. Kalia, L.V., Salter, M.W. Neuropharmacology (2003) [Pubmed]
  20. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Kornau, H.C., Schenker, L.T., Kennedy, M.B., Seeburg, P.H. Science (1995) [Pubmed]
  21. Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity. Ehrlich, I., Malinow, R. J. Neurosci. (2004) [Pubmed]
  22. N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Topinka, J.R., Bredt, D.S. Neuron (1998) [Pubmed]
  23. Synaptic targeting of neuroligin is independent of neurexin and SAP90/PSD95 binding. Dresbach, T., Neeb, A., Meyer, G., Gundelfinger, E.D., Brose, N. Mol. Cell. Neurosci. (2004) [Pubmed]
  24. Differential recruitment of Kv1.4 and Kv4.2 to lipid rafts by PSD-95. Wong, W., Schlichter, L.C. J. Biol. Chem. (2004) [Pubmed]
  25. Hippocampal synaptic plasticity involves competition between Ca2+/calmodulin-dependent protein kinase II and postsynaptic density 95 for binding to the NR2A subunit of the NMDA receptor. Gardoni, F., Schrama, L.H., Kamal, A., Gispen, W.H., Cattabeni, F., Di Luca, M. J. Neurosci. (2001) [Pubmed]
  26. Flavonoids from Radix Scutellariae as potential stroke therapeutic agents by targeting the second postsynaptic density 95 (PSD-95)/disc large/zonula occludens-1 (PDZ) domain of PSD-95. Tang, W., Sun, X., Fang, J.S., Zhang, M., Sucher, N.J. Phytomedicine (2004) [Pubmed]
  27. Synaptic localization of NMDA receptor subunits in the rat retina. Fletcher, E.L., Hack, I., Brandstätter, J.H., Wässle, H. J. Comp. Neurol. (2000) [Pubmed]
  28. Identification of proteins in the postsynaptic density fraction by mass spectrometry. Walikonis, R.S., Jensen, O.N., Mann, M., Provance, D.W., Mercer, J.A., Kennedy, M.B. J. Neurosci. (2000) [Pubmed]
  29. Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin signaling pathway. Lee, C.C., Huang, C.C., Wu, M.Y., Hsu, K.S. J. Biol. Chem. (2005) [Pubmed]
  30. Differential expression of isoforms of PSD-95 binding protein (GKAP/SAPAP1) during rat brain development. Kawashima, N., Takamiya, K., Sun, J., Kitabatake, A., Sobue, K. FEBS Lett. (1997) [Pubmed]
  31. Suppression of postsynaptic density protein 95 expression attenuates increased tyrosine phosphorylation of NR2A subunits of N-methyl-D-aspartate receptors and interactions of Src and Fyn with NR2A after transient brain ischemia in rat hippocampus. Hou, X.Y., Zhang, G.Y., Zong, Y.Y. Neurosci. Lett. (2003) [Pubmed]
  32. Supramodular structure and synergistic target binding of the N-terminal tandem PDZ domains of PSD-95. Long, J.F., Tochio, H., Wang, P., Fan, J.S., Sala, C., Niethammer, M., Sheng, M., Zhang, M. J. Mol. Biol. (2003) [Pubmed]
  33. beta 1-adrenergic receptor association with PSD-95. Inhibition of receptor internalization and facilitation of beta 1-adrenergic receptor interaction with N-methyl-D-aspartate receptors. Hu, L.A., Tang, Y., Miller, W.E., Cong, M., Lau, A.G., Lefkowitz, R.J., Hall, R.A. J. Biol. Chem. (2000) [Pubmed]
  34. Disruption of the NMDA receptor-PSD-95 interaction in hippocampal neurons with no obvious physiological short-term effect. Lim, I.A., Merrill, M.A., Chen, Y., Hell, J.W. Neuropharmacology (2003) [Pubmed]
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