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Gene Review

DLG4  -  discs, large homolog 4 (Drosophila)

Homo sapiens

Synonyms: Disks large homolog 4, PSD-95, PSD95, Postsynaptic density protein 95, SAP-90, ...
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Disease relevance of DLG4


Psychiatry related information on DLG4

  • Abnormalities of PSD95-like molecules and other intracellular signaling machinery may contribute to dysregulated communication between multiple neurotransmitter systems (such as glutamatergic and dopaminergic systems) that are potentially involved in the neurobiology of schizophrenia and affective disorders [4].
  • A down-regulation of PSD-95 in schizophrenia and bipolar disorder may also relate to disease mechanisms of psychosis [5].

High impact information on DLG4

  • In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation [6].
  • In cultured cortical neurons, suppressing the expression of the NMDAR scaffolding protein PSD-95 (postsynaptic density-95) selectively attenuated excitotoxicity triggered via NMDARs, but not by other glutamate or calcium ion (Ca2+) channels [7].
  • PSD-95 may recruit ion channels and neurotransmitter receptors to intercellular junctions formed between neurons by neuroligins and beta-neurexins [8].
  • In mouse forebrain, PSD-95 bound to the cytoplasmic COOH-termini of neuroligins, which are neuronal cell adhesion molecules that interact with beta-neurexins and form intercellular junctions [8].
  • Members of the MAGUK (membrane-associated guanylate kinase) protein family, like PSD-95, use multiple domains to cluster ion channels, receptors, adhesion molecules and cytosolic signaling proteins at synapses, cellular junctions, and polarized membrane domains [9].

Biological context of DLG4

  • DLG4 levels were restored by expression of either E6AP-specific short hairpin RNA or bovine papillomavirus type 1 E2 in HeLa but not CaSki or SiHa cells, reflecting downregulation of DLG4 mRNA as opposed to protein by an HPV-independent mechanism in HPV16-positive cancer lines [10].
  • We have determined the exon-intron organization and characterized the 5'-flanking promoter region of DLG4 [11].
  • Three different exons of DLG4 were found to be alternatively spliced in a subset of tissues [11].
  • DLG4 maps to a region on chromosome 17p13.1 known to contain a locus for autosomal dominant cone dystrophy 5 [11].
  • This upregulation of PSD-95 expression by the Nrg-ICD-Eos complex provides a molecular basis for activity-dependent synaptic plasticity [12].

Anatomical context of DLG4


Associations of DLG4 with chemical compounds


Physical interactions of DLG4

  • RESULTS: We report that PSD-95 interacts with the adenomatous polyposis coli (APC) tumour suppressor protein via its PDZ domain [20].
  • BACKGROUND: The synaptic protein PSD-95/SAP90 interacts with ion channels such as the N-methyl-D-aspartate-receptor (NMDA-R) via its PDZ domain, and is involved in their clustering [20].
  • These last two inhibitors, prevented also NR2B binding to PSD95 [21].
  • CRIPT is a postsynaptic protein that binds selectively to the third PDZ domain (PDZ3) of PSD-95 [22].
  • These proteins include several synaptic multidomain proteins containing one or several PDZ domains (PSD95 and the proteins of the tripartite complex Veli3-CASK-Mint1), proteins of the actin/spectrin cytoskeleton and signalling proteins [23].

Enzymatic interactions of DLG4

  • Expression of polyglutamine-expanded huntingtin induced elevation of phosphorylated or activated Src and increased targeting of PSD-95 (post-synaptic density 95) and activated Src to cell surface membrane [24].

Co-localisations of DLG4

  • Approximately 75 and 90% of GFP-BEGAIN clusters were colocalized with synaptophysin and PSD-95/SAP90, respectively [25].
  • We found that expression of tagged ARHGEF6 in hippocampal slice cultures shows a punctate staining in dendritic spines that colocalizes with PSD95 [26].

Regulatory relationships of DLG4

  • PKC activation and PSD-95 expression each enhance NMDAR channel opening rate and number of functional channels at the cell surface [27].
  • Thus, we propose that GRK5 regulates beta(1)AR association with PSD-95 through phosphorylation of beta(1)AR [28].
  • These results suggest that the microtubule-bundling activity of APC is regulated by its interaction with PSD-95, which might modulate microtubule architecture and dynamics in neurons [29].
  • Immunostaining analysis of cortical cultured neurons revealed that Abeta treatment induces concomitant decreases in PSD-95 at synapses and in the surface expression of the AMPAR glutamate receptor subunit 2 [30].
  • Interestingly, PSD-95-induced dendritic spinogenesis was completely abolished by knock down of SPIN90/WISH [31].

Other interactions of DLG4

  • Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos [12].
  • PSD-95 and PKC each increase NMDAR surface expression, as indicated by immunofluorescence [27].
  • 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 [27].
  • We discuss the possibility that the GKAP/DLC interaction may be involved in trafficking of the PSD-95 complex by motor proteins [13].
  • The SAP97 PDZ2 domain differed at four positions from the other members of the PSD-95 subfamily [19].

Analytical, diagnostic and therapeutic context of DLG4


  1. Antioxidant N-acetylcysteine inhibits the activation of JNK3 mediated by the GluR6-PSD95-MLK3 signaling module during cerebral ischemia in rat hippocampus. Zhang, Q.G., Tian, H., Li, H.C., Zhang, G.Y. Neurosci. Lett. (2006) [Pubmed]
  2. Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence. Gylys, K.H., Fein, J.A., Yang, F., Wiley, D.J., Miller, C.A., Cole, G.M. Am. J. Pathol. (2004) [Pubmed]
  3. Role of the PDZ scaffolding protein in tubule cells in maintenance of polarised function. Glynne, P.A., Evans, T.J. Exp. Nephrol. (2002) [Pubmed]
  4. Abnormalities of the NMDA Receptor and Associated Intracellular Molecules in the Thalamus in Schizophrenia and Bipolar Disorder. Clinton, S.M., Meador-Woodruff, J.H. Neuropsychopharmacology (2004) [Pubmed]
  5. NMDA receptor subunit NRI and postsynaptic protein PSD-95 in hippocampus and orbitofrontal cortex in schizophrenia and mood disorder. Toro, C., Deakin, J.F. Schizophr. Res. (2005) [Pubmed]
  6. Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Migaud, M., Charlesworth, P., Dempster, M., Webster, L.C., Watabe, A.M., Makhinson, M., He, Y., Ramsay, M.F., Morris, R.G., Morrison, J.H., O'Dell, T.J., Grant, S.G. Nature (1998) [Pubmed]
  7. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Sattler, R., Xiong, Z., Lu, W.Y., Hafner, M., MacDonald, J.F., Tymianski, M. Science (1999) [Pubmed]
  8. Binding of neuroligins to PSD-95. Irie, M., Hata, Y., Takeuchi, M., Ichtchenko, K., Toyoda, A., Hirao, K., Takai, Y., Rosahl, T.W., Südhof, T.C. Science (1997) [Pubmed]
  9. Protein modules as organizers of membrane structure. Fanning, A.S., Anderson, J.M. Curr. Opin. Cell Biol. (1999) [Pubmed]
  10. E6AP-dependent degradation of DLG4/PSD95 by high-risk human papillomavirus type 18 E6 protein. Handa, K., Yugawa, T., Narisawa-Saito, M., Ohno, S., Fujita, M., Kiyono, T. J. Virol. (2007) [Pubmed]
  11. Genomic organization of human DLG4, the gene encoding postsynaptic density 95. Stathakis, D.G., Udar, N., Sandgren, O., Andreasson, S., Bryant, P.J., Small, K., Forsman-Semb, K. J. Neurochem. (1999) [Pubmed]
  12. Activity-dependent transcription regulation of PSD-95 by neuregulin-1 and Eos. Bao, J., Lin, H., Ouyang, Y., Lei, D., Osman, A., Kim, T.W., Mei, L., Dai, P., Ohlemiller, K.K., Ambron, R.T. Nat. Neurosci. (2004) [Pubmed]
  13. Interaction of the postsynaptic density-95/guanylate kinase domain-associated protein complex with a light chain of myosin-V and dynein. Naisbitt, S., Valtschanoff, J., Allison, D.W., Sala, C., Kim, E., Craig, A.M., Weinberg, R.J., Sheng, M. J. Neurosci. (2000) [Pubmed]
  14. Cloning and characterization of postsynaptic density 93, a nitric oxide synthase interacting protein. Brenman, J.E., Christopherson, K.S., Craven, S.E., McGee, A.W., Bredt, D.S. J. Neurosci. (1996) [Pubmed]
  15. Erbin is a protein concentrated at postsynaptic membranes that interacts with PSD-95. Huang, Y.Z., Wang, Q., Xiong, W.C., Mei, L. J. Biol. Chem. (2001) [Pubmed]
  16. SAP90 binds and clusters kainate receptors causing incomplete desensitization. Garcia, E.P., Mehta, S., Blair, L.A., Wells, D.G., Shang, J., Fukushima, T., Fallon, J.R., Garner, C.C., Marshall, J. Neuron (1998) [Pubmed]
  17. GKAP, a novel synaptic protein that interacts with the guanylate kinase-like domain of the PSD-95/SAP90 family of channel clustering molecules. Kim, E., Naisbitt, S., Hsueh, Y.P., Rao, A., Rothschild, A., Craig, A.M., Sheng, M. J. Cell Biol. (1997) [Pubmed]
  18. Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95. Sun, Y., Savanenin, A., Reddy, P.H., Liu, Y.F. J. Biol. Chem. (2001) [Pubmed]
  19. Selective interaction of megalin with postsynaptic density-95 (PSD-95)-like membrane-associated guanylate kinase (MAGUK) proteins. Larsson, M., Hjälm, G., Sakwe, A.M., Engström, A., Höglund, A.S., Larsson, E., Robinson, R.C., Sundberg, C., Rask, L. Biochem. J. (2003) [Pubmed]
  20. The colorectal tumour suppressor APC is present in the NMDA-receptor-PSD-95 complex in the brain. Yanai, H., Satoh, K., Matsumine, A., Akiyama, T. Genes Cells (2000) [Pubmed]
  21. Interleukin-1beta Released by gp120 Drives Neural Death through Tyrosine Phosphorylation and Trafficking of NMDA Receptors. Viviani, B., Gardoni, F., Bartesaghi, S., Corsini, E., Facchi, A., Galli, C.L., Di Luca, M., Marinovich, M. J. Biol. Chem. (2006) [Pubmed]
  22. Microtubule binding by CRIPT and its potential role in the synaptic clustering of PSD-95. Passafaro, M., Sala, C., Niethammer, M., Sheng, M. Nat. Neurosci. (1999) [Pubmed]
  23. Synaptic multiprotein complexes associated with 5-HT(2C) receptors: a proteomic approach. Bécamel, C., Alonso, G., Galéotti, N., Demey, E., Jouin, P., Ullmer, C., Dumuis, A., Bockaert, J., Marin, P. EMBO J. (2002) [Pubmed]
  24. Expression of polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N-methyl-D-aspartate receptors. Song, C., Zhang, Y., Parsons, C.G., Liu, Y.F. J. Biol. Chem. (2003) [Pubmed]
  25. Synaptic and nuclear localization of brain-enriched guanylate kinase-associated protein. Yao, I., Iida, J., Nishimura, W., Hata, Y. J. Neurosci. (2002) [Pubmed]
  26. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Nod??-Langlois, R., Muller, D., Boda, B. J. Cell. Sci. (2006) [Pubmed]
  27. PSD-95 and PKC converge in regulating NMDA receptor trafficking and gating. Lin, Y., Jover-Mengual, T., Wong, J., Bennett, M.V., Zukin, R.S. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  28. G protein-coupled receptor kinase 5 regulates beta 1-adrenergic receptor association with PSD-95. Hu, L.A., Chen, W., Premont, R.T., Cong, M., Lefkowitz, R.J. J. Biol. Chem. (2002) [Pubmed]
  29. Microtubule-bundling activity of APC is stimulated by interaction with PSD-95. Takamori, N., Shimomura, A., Senda, T. Neurosci. Lett. (2006) [Pubmed]
  30. Soluble beta-amyloid1-40 induces NMDA-dependent degradation of postsynaptic density-95 at glutamatergic synapses. Roselli, F., Tirard, M., Lu, J., Hutzler, P., Lamberti, P., Livrea, P., Morabito, M., Almeida, O.F. J. Neurosci. (2005) [Pubmed]
  31. SPIN90/WISH interacts with PSD-95 and regulates dendritic spinogenesis via an N-WASP-independent mechanism. Lee, S., Lee, K., Hwang, S., Kim, S.H., Song, W.K., Park, Z.Y., Chang, S. EMBO J. (2006) [Pubmed]
  32. A direct interaction of PSD-95 with 5-HT2A serotonin receptors regulates receptor trafficking and signal transduction. Xia, Z., Gray, J.A., Compton-Toth, B.A., Roth, B.L. J. Biol. Chem. (2003) [Pubmed]
  33. N-methyl-D-aspartic acid receptor expression in the dorsolateral prefrontal cortex of elderly patients with schizophrenia. Dracheva, S., Marras, S.A., Elhakem, S.L., Kramer, F.R., Davis, K.L., Haroutunian, V. The American journal of psychiatry. (2001) [Pubmed]
  34. N-terminal PDZ-binding domain in Kv1 potassium channels. Eldstrom, J., Doerksen, K.W., Steele, D.F., Fedida, D. FEBS Lett. (2002) [Pubmed]
  35. Gene expression of PSD95 in prefrontal cortex and hippocampus in schizophrenia. Ohnuma, T., Kato, H., Arai, H., Faull, R.L., McKenna, P.J., Emson, P.C. Neuroreport (2000) [Pubmed]
  36. Reduction in the number of astrocytes and their projections is associated with increased synaptic protein density in the hypothalamus of poorly controlled diabetic rats. Lechuga-Sancho, A.M., Arroba, A.I., Frago, L.M., Garc??a-C??ceres, C., de C??lix, A.D., Argente, J., Chowen, J.A. Endocrinology (2006) [Pubmed]
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