Disease relevance of DLG4

• Our results indicate that the GluR6-PSD95-MLK3 complex quickly enhanced at 5min of ischemia and peaked at 10min of ischemia, and then gradually reduced with the prolonged time of ischemia [1].
• Synaptic changes in Alzheimer's disease: increased amyloid-beta and gliosis in surviving terminals is accompanied by decreased PSD-95 fluorescence [2].
• PDZ (Postsynaptic density protein 95/Drosophila Disks large/Zona occludens-1) domain-containing proteins have been identified as playing a critical role in membrane trafficking and sorting of ion transporters, receptors and other signalling proteins [3].

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

• DLG4 was found to be expressed in normal human cells, including cervical keratinocytes, but only to a limited extent in both HPV-positive and HPV-negative cervical cancer cell lines [10].
• Here we report that, in the mouse cochlea, synaptic activity increases the level of nuclear Nrg-ICD and upregulates postsynaptic density protein-95 (PSD-95), a scaffolding protein that is enriched in post-synaptic structures [12].
• DLC colocalizes with PSD-95 and F-actin in dendritic spines of cultured neurons and is enriched in biochemical purifications of PSD [13].
• PSD-93, however, is unique among PSD-95/SAP-90 family members in its expression in Purkinje neuron cell bodies and dendrites [14].
• Erbin is a protein concentrated at postsynaptic membranes that interacts with PSD-95 [15].

Associations of DLG4 with chemical compounds

• Similar to NMDA receptors, GluR6 clustering is mediated by the interaction of its C-terminal amino acid sequence, ETMA, with the PDZ1 domain of SAP90 [16].
• SAP90 binds and clusters kainate receptors causing incomplete desensitization [16].
• Although the function of the NH2-terminal PDZ domains is relatively well characterized, the function of the Src homology 3 (SH3) domain and the guanylate kinase-like (GK) domain in the COOH-terminal half of PSD-95 has remained obscure [17].
• Our results demonstrate that polyglutamine expansion impairs the ability of huntingtin to bind PSD-95 and inhibits glutamate-mediated excitotoxicity [18].
• Surface plasmon resonance experiments revealed that mutation of SAP97 Thr(389) to alanine, as with the other PSD-95-like membrane-associated guanylate kinases, induced binding to megalin [19].

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

• Co-immunoprecipitation studies revealed that the native 5-HT2A receptor, but not a mutant lacking the PDZ-binding domain, interacted directly with PSD-95 [32].
• The mRNA expression of the NR(1), NR(2A), and NR(2B) subunits and of postsynaptic density 95 (PSD-95), a protein associated with postsynaptic NMDA receptors, was studied with quantitative real-time reverse transcriptase polymerase chain reaction [33].
• A combination of in vitro binding and yeast two-hybrid assays unexpectedly showed that PDZ domains derived from PSD95 bind both the C- and N-termini of the channels with comparable avidity [34].
• In situ hybridization analysis showed that the expression of PSD95 was significantly decreased in Brodmann area 9 of the prefrontal cortex but not in the hippocampus [35].
• Western blot analysis revealed that postsynaptic density protein 95 and the presynaptic proteins synapsin I and synaptotagmin increased significantly at 8 wk of diabetes, suggesting increased hypothalamic synaptic density [36].

References