Abstract
Dysbindin-1 is a 50-kDa coiled-coil-containing protein encoded by the gene DTNBP1 (dystrobrevin-binding protein 1), a candidate genetic factor for schizophrenia. Genetic variations in this gene confer a susceptibility to schizophrenia through a decreased expression of dysbindin-1. It was reported that dysbindin-1 regulates the expression of presynaptic proteins and the release of neurotransmitters. However, the precise functions of dysbindin-1 are largely unknown. Here, we show that dysbindin-1 is a novel nucleocytoplasmic shuttling protein and translocated to the nucleus upon treatment with leptomycin B, an inhibitor of exportin-1/CRM1-mediated nuclear export. Dysbindin-1 harbors a functional nuclear export signal necessary for its nuclear export, and the nucleocytoplasmic shuttling of dysbindin-1 affects its regulation of synapsin I expression. In brains of sandy mice, a dysbindin-1-null strain that displays abnormal behaviors related to schizophrenia, the protein and mRNA levels of synapsin I are decreased. These findings demonstrate that the nucleocytoplasmic shuttling of dysbindin-1 regulates synapsin I expression and thus may be involved in the pathogenesis of schizophrenia.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / genetics
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Animals
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Antibiotics, Antineoplastic / pharmacology
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Brain / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Nucleus / genetics
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Cell Nucleus / metabolism*
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Cytoplasm / genetics
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Cytoplasm / metabolism*
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Dysbindin
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Dystrophin-Associated Proteins
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Exportin 1 Protein
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Fatty Acids, Unsaturated / pharmacology
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Gene Expression Regulation*
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HEK293 Cells
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Humans
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Karyopherins / antagonists & inhibitors
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Karyopherins / genetics
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Karyopherins / metabolism
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Mice
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Mice, Mutant Strains
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Presynaptic Terminals / metabolism
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism
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Schizophrenia / genetics
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Schizophrenia / metabolism*
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Synapsins / biosynthesis*
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Synapsins / genetics
Substances
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Antibiotics, Antineoplastic
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Carrier Proteins
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DTNBP1 protein, human
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Dtnbp1 protein, mouse
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Dysbindin
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Dystrophin-Associated Proteins
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Fatty Acids, Unsaturated
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Karyopherins
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Synapsins
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leptomycin B