Disease relevance of Dlgh1

• Here, we show that expression and subcellular distribution of PSD-95 and SAP97 are altered in the striatum of unilateral 6-OHDA-lesioned rats following repeated vehicle (a model of PD) or L-DOPA administration (a model of L-DOPA-induced dyskinesia) [1].
• 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) [1].
• Subcellular redistribution of the synapse-associated proteins PSD-95 and SAP97 in animal models of Parkinson's disease and L-DOPA-induced dyskinesia [1].

High impact information on Dlgh1

• Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function [2].
• Biochemical analysis and total internal reflection fluorescence microscopy reveal that the subsequent physical interaction between APC and Dlg1 is required for polarization of the microtubule cytoskeleton [3].
• Light and immunoelectron microscopic analysis of the rat hippocampal formation revealed that SAP97 is localized in the presynaptic nerve termini of excitatory synapses [4].
• In cultured T84 cells, it is restricted to the cytoplasmic surface of the plasma membranes between adjacent cells, but not at the edges of cells lacking cell-cell contact suggesting a role for SAP97 in cell adhesion [4].
• SAP97 is not restricted to the CNS, but is also present at the basal lateral membrane between a variety of epithelial cells [4].

Biological context of Dlgh1

• Moreover, transfection in hippocampal neurons of SAP97 mutants that blocked or mimicked Ser-39 phosphorylation had effects similar to those observed upon inhibiting or constitutively activating CaMKII [5].
• Transfection of activated alphaCaMKII T286D dramatically increased concentration of both endogenous and transfected SAP97 at postsynaptic terminals [5].
• This AKAP79-dependent downregulation is contingent on the local presence of PKA, Ser845 of GluR1, and a PDZ (postsynaptic density 95/Discs large/zona occludens 1)-domain interaction between GluR1 and SAP97, all of which support basal phosphorylation of the receptor [6].
• This superfamily includes the synapse associated protein SAP97, a close relative of SAP90, the Drosophila tumor suppressor gene product dlg-Ap, the mammalian zonula occludens proteins ZO-1 and ZO-2 and the erythrocyte protein p55 [7].
• These results suggest that SAP97 can affect the synaptic recruitment of AMPA receptors and spine morphology and that these effects may be regulated by alternative splicing [8].

Anatomical context of Dlgh1

• CaMKII activation led to increased targeting of SAP97 into dendritic spines, whereas CaMKII inhibition was responsible for SAP97 high colocalization in the cell soma with the endoplasmic reticulum protein disulfide-isomerase [5].
• Post L-DOPA treatment, PSD-95 and SAP97 levels increased (367.4 +/- 43.2% and 159.9 +/- 9.5% from control values, respectively), with both being redistributed toward synaptic membranes from vesicular compartments [1].
• Synapse-associated protein-97 (SAP97) mRNA levels were increased in the entorhinal cortex layer III after MK-801 or after relatively high doses of other uncompetitive NMDA receptor antagonists: phencyclidine (15 mg/kg; 6 hr) and memantine (50 mg/kg; 6 hr) [9].
• SAP97, a PDZ-containing protein, is reported to concentrate in axon terminals, where its function remains unknown [10].
• SAP97 concentrates at the postsynaptic density in cerebral cortex [10].

Associations of Dlgh1 with chemical compounds

• Synapse-associated protein 97 (SAP97) has been involved in the correct delivery and clustering of glutamate ionotropic receptors to the postsynaptic compartment [5].
• Memantine also increased SAP97 mRNA expression in other cortical regions, but this effect was not observed with MK-801 or phencyclidine [9].
• The NR2B subunit interacts with post-synaptic density protein 95 (PSD-95), SAP97 and members of the membrane-associated guanylate-like kinase (MAGUK) family of proteins [11].
• Differential interaction of the tSXV motifs of the NR1 and NR2A NMDA receptor subunits with PSD-95 and SAP97 [11].
• Thus, it would appear that the GK domain of SAP97 is not involved in the metabolism of guanine nucleotides required for signaling events [12].

Physical interactions of Dlgh1

• SAP97 interacts with Kv1.5 in heterologous expression systems [13].

Regulatory relationships of Dlgh1

• Blockade of calpain activity reduced CX614-induced degradation of SAP97 and GRIP1 and prevented decreases in AMPAr subunit but not mRNA levels [14].

Other interactions of Dlgh1

• These events are paralleled by profound modifications of NMDA receptor NR2B subunit association with interacting elements, i.e., members of the membrane-associated guanylate kinase (MAGUK) protein family postsynaptic density-95, synapse-associated protein-97 and synapse-associated protein-102 [15].
• Here we demonstrate that synaptic trafficking of SAP97 itself was modulated by calcium/calmodulin-dependent protein kinase II (CaMKII) in cultured hippocampal neurons [5].
• From heart extract purifications, SAP97, CASK, Veli-3, and Mint1 also were found to associate with Kir2 channels [16].
• Decline in SAP97 and GRIP1 levels was associated with increased abundance of lower molecular weight bands, suggesting degradation of these proteins [14].
• Synapse-associated proteins (SAPs), for example, PSD-95 and SAP97 organize the molecular architecture of synapses and regulate interactions between receptors and downstream-signaling molecules [1].

Analytical, diagnostic and therapeutic context of Dlgh1

• In situ hybridization showed that changes in total levels of PSD-95, but not SAP97, were accompanied by qualitatively similar changes in mRNA [1].
• Using immunohistochemistry, we also compared the distribution of the PSD-95, NR2A and SAP97 proteins in adult rat brain, and we show that in the cortex, hippocampus and cerebellum, there is evidence for colocalization of these proteins [11].
• Using quantitative postembedding immunogold electron microscopy, we find that SAP97 is at highest concentration within the postsynaptic density of asymmetric synapses [10].
• Using the two-hybrid genetic system in yeast and site-directed mutagenesis, we compared the binding of the NR2A, NR1-3 and NR1-4 tSXV motifs with the PDZ domains of PSD-95 and SAP97 [11].
• Immunoprecipitation confirms a direct binding of SAP 97 and ezrin [17].

References