Alternative titles; symbols
HGNC Approved Gene Symbol: DLGAP3
Cytogenetic location: 1p34.3 Genomic coordinates (GRCh38) : 1:34,865,436-34,929,650 (from NCBI)
Takeuchi et al. (1997) cloned rat Dlgap3, which they called Sapap3. The deduced 977-amino acid protein has a central proline-rich region and a conserved C-terminal domain that includes a second proline-rich region. Northern blot analysis detected high expression of a 5-kb Sapap3 transcript in rat brain. Immunohistochemical analysis of cultured primary embryonic rat hippocampal neurons detected Sapap3 expression in dendrites, cell bodies, and nuclei. Western blot analysis of fractionated rat brain detected Sapap3 enriched in synaptosomes.
Using a segment of rat Fak (PTK2; 600758) to screen an adult human brain cDNA library, Bongiorno-Borbone et al. (2005) cloned DLGAP3, which they called SAPAP3. The deduced protein contains 977 amino acids.
Hartz (2015) mapped the DLGAP3 gene to chromosome 1p34.3 based on an alignment of the DLGAP3 sequence (GenBank AF131778) with the genomic sequence (GRCh38).
Using yeast 2-hybrid analysis, Takeuchi et al. (1997) determined that rat Sapap3 interacted with the SH3 domains of Psd95, Sap97 (DLG1; 601014), Sapap1 (DLGAP1; 605445), and Dlg-A (MPP2; 600723), but not with other membrane-associated guanylate kinases examined. Coexpression of Sapap3 with Psd95 in HEK293 cells caused accumulation of cytosolic Psd95 at the plasma membrane.
By mutation analysis, Bongiorno-Borbone et al. (2005) demonstrated that the N-terminal half of human SAPAP3 interacted with a C-terminal segment of rat Fak. They also found that SAPAP3 interacted with Pyk2 (PTK2B; 601212) in in vitro pull-down assays. In rat forebrain lysates, part of Fak and Pyk2 had a similar subcellular distribution as Sapap3 and Sap90/Psd95, which supported their functional association.
Welch et al. (2007) generated Sapap3-deficient mice and found that they had increased anxiety and compulsive grooming behavior leading to facial hair loss (e.g., trichotillomania; 613229) and skin lesions; both behaviors were alleviated by a selective serotonin reuptake inhibitor. Electrophysiologic, structural, and biochemical studies of Sapap3 mutant mice revealed defects in corticostriatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescued the synaptic and behavioral defects of Sapap3 mutant mice. Welch et al. (2007) concluded that their findings demonstrated a critical role for Sapap3 at corticostriatal synapses and emphasized the importance of corticostriatal circuitry in obsessive-compulsive-like behaviors.
Burguiere et al. (2013) developed an optogenetic approach to block repetitive, compulsive behavior in a mouse model in which deletion of the synaptic scaffolding gene Sapap3 results in excessive grooming. With a delay-conditioning task, Burguiere et al. (2013) identified in the mutants a selective deficit in behavioral response inhibition and found this to be associated with defective downregulation of striatal projection neuron activity. Focused optogenetic stimulation of the lateral orbitofrontal cortex and its terminals in the striatum restored the behavioral response inhibition, restored the defective downregulation, and compensated for impaired fast-spiking neuron striatal microcircuits.
Bongiorno-Borbone, L., Kadare, G., Benfanati, F., Girault, J.-A. FAK and PYK2 interact with SAP90/PSD-95-associated protein-3. Biochem. Biophys. Res. Commun. 337: 641-666, 2005. [PubMed: 16202977] [Full Text: https://doi.org/10.1016/j.bbrc.2005.09.099]
Burguiere, E., Monteiro, P., Feng, G., Graybiel, A. M. Optogenetic stimulation of lateral orbitofronto-striatal pathway suppresses compulsive behaviors. Science 340: 1243-1246, 2013. [PubMed: 23744950] [Full Text: https://doi.org/10.1126/science.1232380]
Hartz, P. A. Personal Communication. Baltimore, Md. 2/2/2015.
Takeuchi, M., Hata, Y., Hirao, K., Toyoda, A., Irie, M., Takai, Y. SAPAPs: a family of PSD-95/SAP90-associated proteins localized at postsynaptic density. J. Biol. Chem. 272: 11943-11951, 1997. [PubMed: 9115257] [Full Text: https://doi.org/10.1074/jbc.272.18.11943]
Welch, J. M., Lu, J., Rodriguiz, R. M., Trotta, N. C., Peca, J., Ding, J.-D., Feliciano, C., Chen, M., Adams, J. P., Luo, J., Dudek, S. M., Weinberg, R. J., Calakos, N., Wetsel, W. C., Feng, G. Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice. Nature 448: 894-900, 2007. [PubMed: 17713528] [Full Text: https://doi.org/10.1038/nature06104]