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Gene Review

Dlg1  -  discs, large homolog 1 (Drosophila)

Rattus norvegicus

Synonyms: Disks large homolog 1, Dlgh1, SAP-97, SAP97, Synapse-associated protein 97
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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


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


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


  1. 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]
  2. Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. Schlüter, O.M., Xu, W., Malenka, R.C. Neuron (2006) [Pubmed]
  3. Cdc42 and Par6-PKCzeta regulate the spatially localized association of Dlg1 and APC to control cell polarization. Etienne-Manneville, S., Manneville, J.B., Nicholls, S., Ferenczi, M.A., Hall, A. J. Cell Biol. (2005) [Pubmed]
  4. Molecular characterization and spatial distribution of SAP97, a novel presynaptic protein homologous to SAP90 and the Drosophila discs-large tumor suppressor protein. Müller, B.M., Kistner, U., Veh, R.W., Cases-Langhoff, C., Becker, B., Gundelfinger, E.D., Garner, C.C. J. Neurosci. (1995) [Pubmed]
  5. Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines. Mauceri, D., Cattabeni, F., Di Luca, M., Gardoni, F. J. Biol. Chem. (2004) [Pubmed]
  6. Regulation of GluR1 by the A-kinase anchoring protein 79 (AKAP79) signaling complex shares properties with long-term depression. Tavalin, S.J., Colledge, M., Hell, J.W., Langeberg, L.K., Huganir, R.L., Scott, J.D. J. Neurosci. (2002) [Pubmed]
  7. Nucleotide binding by the synapse associated protein SAP90. Kistner, U., Garner, C.C., Linial, M. FEBS Lett. (1995) [Pubmed]
  8. Synapse-associated protein-97 isoform-specific regulation of surface AMPA receptors and synaptic function in cultured neurons. Rumbaugh, G., Sia, G.M., Garner, C.C., Huganir, R.L. J. Neurosci. (2003) [Pubmed]
  9. Uncompetitive antagonists of the N-methyl-D-aspartate (NMDA) receptors alter the mRNA expression of proteins associated with the NMDA receptor complex. Lindén, A.M., Väsänen, J., Storvik, M., Lakso, M., Korpi, E.R., Wong, G., Castrén, E. Pharmacol. Toxicol. (2001) [Pubmed]
  10. SAP97 concentrates at the postsynaptic density in cerebral cortex. Valtschanoff, J.G., Burette, A., Davare, M.A., Leonard, A.S., Hell, J.W., Weinberg, R.J. Eur. J. Neurosci. (2000) [Pubmed]
  11. Differential interaction of the tSXV motifs of the NR1 and NR2A NMDA receptor subunits with PSD-95 and SAP97. Bassand, P., Bernard, A., Rafiki, A., Gayet, D., Khrestchatisky, M. Eur. J. Neurosci. (1999) [Pubmed]
  12. Functional analysis of the guanylate kinase-like domain in the synapse-associated protein SAP97. Kuhlendahl, S., Spangenberg, O., Konrad, M., Kim, E., Garner, C.C. Eur. J. Biochem. (1998) [Pubmed]
  13. SAP97 interacts with Kv1.5 in heterologous expression systems. Murata, M., Buckett, P.D., Zhou, J., Brunner, M., Folco, E., Koren, G. Am. J. Physiol. Heart Circ. Physiol. (2001) [Pubmed]
  14. Prolonged positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induces calpain-mediated PSD-95/Dlg/ZO-1 protein degradation and AMPA receptor down-regulation in cultured hippocampal slices. Jourdi, H., Lu, X., Yanagihara, T., Lauterborn, J.C., Bi, X., Gall, C.M., Baudry, M. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  15. A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. Gardoni, F., Picconi, B., Ghiglieri, V., Polli, F., Bagetta, V., Bernardi, G., Cattabeni, F., Di Luca, M., Calabresi, P. J. Neurosci. (2006) [Pubmed]
  16. Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2.x)-associated proteins. Leonoudakis, D., Conti, L.R., Anderson, S., Radeke, C.M., McGuire, L.M., Adams, M.E., Froehner, S.C., Yates, J.R., Vandenberg, C.A. J. Biol. Chem. (2004) [Pubmed]
  17. SAP 97 is a potential candidate for basolateral fixation of ezrin in parietal cells. Jöns, T., Heim, H.K., Kistner, U., Ahnert-Hilger, G. Histochem. Cell Biol. (1999) [Pubmed]
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