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RISS 인기검색어
- 검색키워드
- 저자 : Kunitoshi Uchida (검색결과 2 건)
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Jang, Yongwoo,Lee, Sung Hoon,Lee, Byeongjun,Jung, Seungmoon,Khalid, Arshi,Uchida, Kunitoshi,Tominaga, Makoto,Jeon, Daejong,Oh, Uhtaek Society for Neuroscience 2015 The Journal of neuroscience Vol.35 No.34
<P>Bipolar disorder (BD) is a psychiatric disease that causes mood swings between manic and depressed states. Although genetic linkage studies have shown an association between BD and TRPM2, a Ca<SUP>2+</SUP>-permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of <I>Trpm2</I> that is frequently found in BD patients, induces loss of function. <I>Trpm2</I>-deficient mice exhibited BD-related behavior such as increased anxiety and decreased social responses, along with disrupted EEG functional connectivity. Moreover, the administration of amphetamine in wild-type mice evoked a notable increase in open-field activity that was reversed by the administration of lithium. However, the anti-manic action of lithium was not observed in the <I>Trpm2</I><SUP>−/−</SUP> mice. The brains of <I>Trpm2</I><SUP>−/−</SUP> mice showed a marked increase in phosphorylated glycogen synthase kinase-3 (GSK-3), a key element in BD-like behavior and a target of lithium. In contrast, activation of TRPM2 induced the dephosphorylation of GSK-3 via calcineurin, a Ca<SUP>2+</SUP>-dependent phosphatase. Importantly, the overexpression of the D543E mutant failed to induce the dephosphorylation of GSK-3. Therefore, we conclude that the genetic dysfunction of <I>Trpm2</I> causes uncontrolled phosphorylation of GSK-3, which may lead to the pathology of BD. Our findings explain the long-sought etiologic mechanism underlying the genetic link between <I>Trpm2</I> mutation and BD.</P><P><B>SIGNIFICANCE STATEMENT</B> Bipolar disorder (BD) is a mental disorder that causes changes in mood and the etiology is still unknown. TRPM2 is highly associated with BD; however, its involvement in the etiology of BD is still unknown. We show here that TRPM2 plays a central role in causing the pathology of BD. We found that D543E, a mutation of <I>Trpm2</I> frequently found in BD patients, induces the loss of function. <I>Trpm2</I>-deficient mice exhibited mood disturbances and impairments in social cognition. TRPM2 actively regulates the phosphorylation of GSK-3, which is a main target of lithium, a primary medicine for treating BD. Therefore, abnormal regulation of GSK-3 by hypoactive TRPM2 mutants accounts for the pathology of BD, providing the possible link between BD and TRPM2.</P>
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