{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1362262943343944576.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1523/jneurosci.1689-07.2007"}},{"identifier":{"@type":"URI","@value":"https://syndication.highwire.org/content/doi/10.1523/JNEUROSCI.1689-07.2007"}}],"dc:title":[{"@value":"Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D<sub>2</sub>Receptor Internalization and Signaling But Not D<sub>1</sub>Internalization"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:p>The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (<jats:italic>DTNBP1</jats:italic>) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D<jats:sub>2</jats:sub>receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D<jats:sub>1</jats:sub>receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in<jats:italic>DTNBP1</jats:italic>, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1380579819070262144","@type":"Researcher","foaf:name":[{"@value":"Yukihiko Iizuka"}]},{"@id":"https://cir.nii.ac.jp/crid/1380579819070262146","@type":"Researcher","foaf:name":[{"@value":"Yoshitatsu Sei"}]},{"@id":"https://cir.nii.ac.jp/crid/1380579819070262147","@type":"Researcher","foaf:name":[{"@value":"Daniel R. Weinberger"}]},{"@id":"https://cir.nii.ac.jp/crid/1380579819070262145","@type":"Researcher","foaf:name":[{"@value":"Richard E. Straub"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"02706474"},{"@type":"EISSN","@value":"15292401"}],"prism:publicationName":[{"@value":"The Journal of Neuroscience"}],"dc:publisher":[{"@value":"Society for Neuroscience"}],"prism:publicationDate":"2007-11-07","prism:volume":"27","prism:number":"45","prism:startingPage":"12390","prism:endingPage":"12395"},"reviewed":"false","dc:rights":["https://creativecommons.org/licenses/by-nc-sa/4.0/"],"url":[{"@id":"https://syndication.highwire.org/content/doi/10.1523/JNEUROSCI.1689-07.2007"}],"createdAt":"2007-11-07","modifiedAt":"2023-04-13","relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360004232391763584","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Dysfunction of dopamine release in the prefrontal cortex of dysbindin deficient sandy mice: An in vivo microdialysis study"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004233981757824","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Disrupted-in-schizophrenia 1 (DISC1) Regulates Dysbindin Function by Enhancing Its Stability"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004236837460480","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Behavioral characterization of mice overexpressing human dysbindin-1"}]},{"@id":"https://cir.nii.ac.jp/crid/1360004237487542400","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Correlated Alterations in Serotonergic and Dopaminergic Modulations at the Hippocampal Mossy Fiber Synapse in Mice Lacking Dysbindin"}]},{"@id":"https://cir.nii.ac.jp/crid/1360567183369845120","@type":"Article","resourceType":"学術雑誌論文(journal article)","relationType":["isReferencedBy"],"jpcoar:relatedTitle":[{"@value":"Dysbindin-1, WAVE2 and Abi-1 form a complex that regulates dendritic spine formation"}]}],"dataSourceIdentifier":[{"@type":"CROSSREF","@value":"10.1523/jneurosci.1689-07.2007"},{"@type":"CROSSREF","@value":"10.1074/jbc.m114.614750_references_DOI_w6gy5WFw6hYTbqsBTne6I7r9Oj"},{"@type":"CROSSREF","@value":"10.1186/s13041-014-0074-x_references_DOI_w6gy5WFw6hYTbqsBTne6I7r9Oj"},{"@type":"CROSSREF","@value":"10.1371/journal.pone.0018113_references_DOI_w6gy5WFw6hYTbqsBTne6I7r9Oj"},{"@type":"CROSSREF","@value":"10.1038/mp.2010.69_references_DOI_w6gy5WFw6hYTbqsBTne6I7r9Oj"},{"@type":"CROSSREF","@value":"10.1016/j.neulet.2009.12.071_references_DOI_w6gy5WFw6hYTbqsBTne6I7r9Oj"}]}