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Gene Review

Dlg4  -  discs, large homolog 4 (Drosophila)

Mus musculus

Synonyms: Disks large homolog 4, Dlgh4, PSD-95, PSD95, Postsynaptic density protein 95, ...
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Disease relevance of Dlg4

  • Using mutant mice expressing a truncated form of the PSD-95 molecule, we show their failure to develop the NMDA receptor-dependent hyperalgesia and allodynia seen in the CCI model of neuropathic pain, but normal inflammatory nociceptive behavior following the injection of formalin [1].

Psychiatry related information on Dlg4


High impact information on Dlg4

  • Here, we isolated 23 mammalian DHHC proteins and found that a subset specifically palmitoylated PSD-95 in vitro and in vivo [3].
  • These PSD-95 palmitoyl transferases (P-PATs) showed substrate specificity, as they did not all enhance palmitoylation of Lck, SNAP-25b, Galpha(s), or H-Ras in cultured cells [3].
  • One of these genes encoding the synaptic scaffolding protein PSD-95 is downregulated in the striatum of all three mutants and in chronically, but not acutely, cocaine-treated mice [4].
  • Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity [4].
  • At the synaptic level, enhanced long-term potentiation (LTP) of the frontocortico-accumbal glutamatergic synapses correlates with PSD-95 reduction in every case [4].

Biological context of Dlg4

  • We also demonstrate that the mRNA for PSD-95, a scaffolding protein involved in synaptic plasticity, contains a highly conserved canonical binding site for FMRP within its 3' UTR [2].
  • Quantitatively, the number of SV2-labeled contacts per neuron at day 5 and the number of PSD-95 clusters per dendrite length at day 18 in culture showed no significant differences between genotypes [5].
  • NR2B and SynGAP homozygote mice die within the first week of birth whereas PSD-95 homozygote mice survive to adulthood [6].
  • While NMDAR1-4 may be related to receptor targeting and clustering to PSD95 and to nNOS, our data suggest that differences in nNOS expression obviously do not directly influence gene expression of this particular NMDAR splice variant [7].
  • Thus, we investigated whether Slo2 channels bind to PSD-95, because it is well known that other types of K+ channels, voltage-gated and inward rectifier K+ channels, bind to PSD-95 via the PDZ binding motif and are involved in excitatory synaptic transmission [8].

Anatomical context of Dlg4

  • The SAPAPs, identified by their direct interaction with PSD-95 family proteins, were initially proposed to function in the anchoring/signaling complex as linker proteins between glutamate receptor binding proteins and the cytoskeleton [9].
  • On the other hand, PSD-95 in axon terminals of cerebellar basket cells, where high levels of potassium channels are present, was detectable irrespective of pepsin pretreatment, suggesting that PSD-95 antibody is readily accessible to the presynaptic epitopes [10].
  • In the cultured cortical neurons from fyn(-/-) mice, dendrites bear few spines, and Sema3A does not induce PSD-95 cluster formation on the dendrites [11].
  • We here show that Sema3A induces clustering of both postsynaptic density-95 (PSD-95) and presynaptic synapsin I in cultured cortical neurons without changing the density of spines or filopodia [11].
  • Citron colocalization with PSD-95 occurred, not exclusively but certainly, at glutamatergic synapses in a limited set of neurons, such as the thalamic excitatory neurons; Citron expression, however, could not be detected in the principal neurons of the hippocampus and the cerebellum in the adult mouse brain [12].

Associations of Dlg4 with chemical compounds

  • In order to study the role of tyrosine kinase signaling in the post-synaptic density (PSD), tyrosine-phosphorylated proteins associated with the PSD-95/NMDA receptor complex were analyzed [13].
  • Among the earliest changes in synaptic composition in APP mutant neurons were reductions in PSD-95, a protein involved in recruiting and anchoring glutamate receptor subunits to the post-synaptic density [14].
  • Since this complex was extracted using Triton X-100 and was devoid of PSD95, SAP97, and actin we postulate that LC2 is involved in trafficking of AMPA receptors in cerebellar neurons before they are anchored at the synapse [15].
  • At excitatory synapses, the postsynaptic scaffolding protein postsynaptic density 95 (PSD-95) couples NMDA receptors (NMDARs) to the Ras GTPase-activating protein SynGAP [16].
  • The enzymes that mediate palmitoyl acyl transfer to PSD-95 have not yet been identified; however, proteins containing a DHHC cysteine-rich domain mediate palmitoyl acyl transferase activity in yeast [3].

Physical interactions of Dlg4


Enzymatic interactions of Dlg4


Co-localisations of Dlg4

  • Medium spiny neurons coexpressed CaV1.3-interacting Shank isoforms that colocalized with PSD-95 and CaV1.3a channels in puncta resembling spines on which glutamatergic corticostriatal synapses are formed [19].

Other interactions of Dlg4

  • A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin [20].
  • When the cultured neurons are exposed to Sema3A, the cluster size of PSD-95 is markedly enhanced, and an extensive colocalization of PSD-95 and NRP-1 or actin-rich protrusion is seen [11].
  • Second, the resulting overall distributions of PSD-95, SAP102, and Chapsyn-110 in the adult mouse brain were consistent with their mRNA distributions [10].
  • The extreme C terminus of stargazin (sequence, -TTPV), confers high affinity for PDZ domain-containing proteins e.g. PSD-95 [15].
  • Finally, we show that these mGluR-dependent changes in PSD-95 expression are lost in neurons derived from FMRP knockout mice, a model of FXS [2].

Analytical, diagnostic and therapeutic context of Dlg4


  1. Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice. Garry, E.M., Moss, A., Delaney, A., O'Neill, F., Blakemore, J., Bowen, J., Husi, H., Mitchell, R., Grant, S.G., Fleetwood-Walker, S.M. Curr. Biol. (2003) [Pubmed]
  2. The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95. Todd, P.K., Mack, K.J., Malter, J.S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  3. Identification of PSD-95 palmitoylating enzymes. Fukata, M., Fukata, Y., Adesnik, H., Nicoll, R.A., Bredt, D.S. Neuron (2004) [Pubmed]
  4. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Yao, W.D., Gainetdinov, R.R., Arbuckle, M.I., Sotnikova, T.D., Cyr, M., Beaulieu, J.M., Torres, G.E., Grant, S.G., Caron, M.G. Neuron (2004) [Pubmed]
  5. Synapse formation by hippocampal neurons from agrin-deficient mice. Serpinskaya, A.S., Feng, G., Sanes, J.R., Craig, A.M. Dev. Biol. (1999) [Pubmed]
  6. Differential expression of two NMDA receptor interacting proteins, PSD-95 and SynGAP during mouse development. Porter, K., Komiyama, N.H., Vitalis, T., Kind, P.C., Grant, S.G. Eur. J. Neurosci. (2005) [Pubmed]
  7. Differential expression of alternatively spliced isoforms of neuronal nitric oxide synthase (nNOS) and N-methyl-D-aspartate receptors (NMDAR) in knockout mice deficient in nNOS alpha (nNOS alpha(Delta/Delta) mice). Putzke, J., Seidel, B., Huang, P.L., Wolf, G. Brain Res. Mol. Brain Res. (2000) [Pubmed]
  8. Slo2 sodium-activated K+ channels bind to the PDZ domain of PSD-95. Uchino, S., Wada, H., Honda, S., Hirasawa, T., Yanai, S., Nakamura, Y., Ondo, Y., Kohsaka, S. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  9. Differential mRNA expression and protein localization of the SAP90/PSD-95-associated proteins (SAPAPs) in the nervous system of the mouse. Welch, J.M., Wang, D., Feng, G. J. Comp. Neurol. (2004) [Pubmed]
  10. Improved immunohistochemical detection of postsynaptically located PSD-95/SAP90 protein family by protease section pretreatment: a study in the adult mouse brain. Fukaya, M., Watanabe, M. J. Comp. Neurol. (2000) [Pubmed]
  11. Regulation of dendritic branching and spine maturation by semaphorin3A-Fyn signaling. Morita, A., Yamashita, N., Sasaki, Y., Uchida, Y., Nakajima, O., Nakamura, F., Yagi, T., Taniguchi, M., Usui, H., Katoh-Semba, R., Takei, K., Goshima, Y. J. Neurosci. (2006) [Pubmed]
  12. Citron, a Rho-target, interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus. Furuyashiki, T., Fujisawa, K., Fujita, A., Madaule, P., Uchino, S., Mishina, M., Bito, H., Narumiya, S. J. Neurosci. (1999) [Pubmed]
  13. Identification of PSD-93 as a substrate for the Src family tyrosine kinase Fyn. Nada, S., Shima, T., Yanai, H., Husi, H., Grant, S.G., Okada, M., Akiyama, T. J. Biol. Chem. (2003) [Pubmed]
  14. Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Almeida, C.G., Tampellini, D., Takahashi, R.H., Greengard, P., Lin, M.T., Snyder, E.M., Gouras, G.K. Neurobiol. Dis. (2005) [Pubmed]
  15. Microtubule-associated protein light chain 2 is a stargazin-AMPA receptor complex-interacting protein in vivo. Ives, J.H., Fung, S., Tiwari, P., Payne, H.L., Thompson, C.L. J. Biol. Chem. (2004) [Pubmed]
  16. SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor. Komiyama, N.H., Watabe, A.M., Carlisle, H.J., Porter, K., Charlesworth, P., Monti, J., Strathdee, D.J., O'Carroll, C.M., Martin, S.J., Morris, R.G., O'Dell, T.J., Grant, S.G. J. Neurosci. (2002) [Pubmed]
  17. Neonatal hypoxia-ischemia differentially upregulates MAGUKs and associated proteins in PSD-93-deficient mouse brain. Jiang, X., Mu, D., Sheldon, R.A., Glidden, D.V., Ferriero, D.M. Stroke (2003) [Pubmed]
  18. Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. Morabito, M.A., Sheng, M., Tsai, L.H. J. Neurosci. (2004) [Pubmed]
  19. G-protein-coupled receptor modulation of striatal CaV1.3 L-type Ca2+ channels is dependent on a Shank-binding domain. Olson, P.A., Tkatch, T., Hernandez-Lopez, S., Ulrich, S., Ilijic, E., Mugnaini, E., Zhang, H., Bezprozvanny, I., Surmeier, D.J. J. Neurosci. (2005) [Pubmed]
  20. A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Prange, O., Wong, T.P., Gerrow, K., Wang, Y.T., El-Husseini, A. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  21. Isolation of 2000-kDa complexes of N-methyl-D-aspartate receptor and postsynaptic density 95 from mouse brain. Husi, H., Grant, S.G. J. Neurochem. (2001) [Pubmed]
  22. Age-related loss of synapses in the frontal cortex of SAMP10 mouse: a model of cerebral degeneration. Shimada, A., Keino, H., Satoh, M., Kishikawa, M., Hosokawa, M. Synapse (2003) [Pubmed]
  23. Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins. Nithianantharajah, J., Levis, H., Murphy, M. Neurobiology of learning and memory. (2004) [Pubmed]
  24. Synaptic targeting by Alzheimer's-related amyloid beta oligomers. Lacor, P.N., Buniel, M.C., Chang, L., Fernandez, S.J., Gong, Y., Viola, K.L., Lambert, M.P., Velasco, P.T., Bigio, E.H., Finch, C.E., Krafft, G.A., Klein, W.L. J. Neurosci. (2004) [Pubmed]
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