title: TRPM2, a Susceptibility Gene for Bipolar Disorder, Regulates Glycogen Synthase Kinase-3 Activity in the Brain.
abstract: 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(2+)-permeable cation channel, the nature of this association is unknown. Here, we show that D543E, a mutation of Trpm2 that is frequently found in BD patients, induces loss of function. Trpm2-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 Trpm2(-/-) mice. The brains of Trpm2(-/-) 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(2+)-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 Trpm2 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 Trpm2 mutation and BD.
  
  
  CONCLUSIONS
  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 Trpm2 frequently found in BD patients, induces the loss of function. Trpm2-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.
authors: Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Yongwoo
authors: Y
authors: Jang
authors: Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Sung Hoon
authors: SH
authors: Lee
authors: Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors: Byeongjun
authors: B
authors: Lee
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors: Seungmoon
authors: S
authors: Jung
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors: Arshi
authors: A
authors: Khalid
authors: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, Okazaki 444-8787, Japan.
authors: Kunitoshi
authors: K
authors: Uchida
authors: Division of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institute for Physiological Sciences, Okazaki 444-8787, Japan.
authors: Makoto
authors: M
authors: Tominaga
authors: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul 110-744, Republic of Korea, and utoh@snu.ac.kr clark.jeon@gmail.com.
authors: Daejong
authors: D
authors: Jeon
authors: Sensory Research Center, Creative Research Initiatives, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea, Institut Pasteur Korea, Sungnam-Si, Gyunggi-Do 463-400, Republic of Korea utoh@snu.ac.kr clark.jeon@gmail.com.
authors: Uhtaek
authors: U
authors: Oh
mesh_terms: D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000502:physiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050053:TRPM Cation Channels / Q000235:genetics / Q000502:physiology*
chemical_list: D050053:TRPM Cation Channels; C121934:TRPM2 protein, human; D038362:Glycogen Synthase Kinase 3
keywords: TRPM2; bipolar disorder; calcineurin; glycogen synthase kinase-3; mutation; susceptibilty