Molecular biological study on the pathophysiology of bipolar disorders

双相情感障碍病理生理学的分子生物学研究

• 批准号: 15591206
• 负责人: KUSUMI Ichiro
• 金额: $ 2.24万
• 依托单位: HOKKAIDO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15591206/
• 关键词: Bipolar disorder; Ca-ATPase pump (SERCA); Proteinkinase C; Calmojurin; Thapsigargin; ATP2A2 gene; XBP1 gene; Ca mobilization; カルシウム; 血小板; 小胞体ストレス反応; セロトニン; TCI; NEO-FFI; ATP2A2遺伝子変異; 一過性細胞質内カルシウム増加; 容量依存性カルシウム流入

We examined thapsigargin (microsomal Ca-ATPase inhibitor)-induced transient intraplatelet calcium increase (TCI) and capcitative calcium entry (CCE) in the patients with bipolar disorder and major depressive disorder, and normal controls. There was no significant difference in thapsigargin-induced TCI or CCE among the three groups. However, in bipolar disorders, the inhibitory effect of proteinkinase C (PKC) stimulator on CCE was increased, and the stimulatory effect of PKC inhibitor on CCE was decreased. No significant differences in the effect of calmodulin inhibitor were observed among the three groups. These results suggest that the PKC function in bipolar disorders is compensatively enhanced to maintain the homeostasis of intracellular calcium (Ca) concentrations.Enhanced Ca mobilization to various agonists in peripheral blood cells in one of a few confirmed biological markers for bipolar disorders. Recently, a polymorphism of XBP1, a pivotal gene in the endoplasmic reticulum stress response, was shown to contribute to the genetic risk factor for bipolar disorder. Thus, in this study, we examined the relationship between the XBP1 gene polymorphism and the Ca signaling in the platelets of healthy subjects. The present results suggest no significant difference in the basal Ca level or serotonin-induced Ca mobilization among normal subjects with -116C/C, C/G, G/G genotypes.

我们研究了双相情感障碍和抑郁症患者以及正常对照组中毒胡萝卜素（微粒体Ca-ATP酶抑制剂）诱导的短暂血小板内钙升高（TCI）和捕获性钙内流（CCE）。三组间毒扁豆碱诱导的TCI或CCE无显著差异。而在双相情感障碍中，蛋白激酶C（PKC）激动剂对CCE的抑制作用增强，而PKC抑制剂对CCE的刺激作用减弱。三组间钙调素抑制剂的作用无显著差异。这些结果表明，PKC功能在双相情感障碍是代偿性增强，以维持细胞内钙（Ca）浓度的稳态。增强的Ca动员各种激动剂在外周血细胞中的双相情感障碍的几个确认的生物标志物之一。最近，一个多态性的XBP 1，一个关键基因在内质网应激反应，被证明有助于遗传风险因素双相情感障碍。因此，在这项研究中，我们研究了健康受试者血小板中的XBP 1基因多态性和Ca信号之间的关系。结果表明，-116 C/C、C/G、G/G基因型正常人的基础钙水平和降钙素诱导的钙动员无显著差异。

项目成果

Suzuki K: "Effects of lithium and valproate on agonist-induced platelet intracellular calcium mobilization : relevance to myosin light chain kinase"Prog Neuro-Psychopharmacol & Biol Psychiatry. 28. 67-72 (2004)

铃木 K：“锂和丙戊酸盐对激动剂诱导的血小板细胞内钙动员的影响：与肌球蛋白轻链激酶的相关性”Prog Neuro-Psychopharmacol

Suzuki K: "Altered 5-HT-induced calcium response in the presence of staurosporine in blood platelets from bipolar disorder patients"Neuropsychoparmacology. 28. 1210-1214 (2003)

Suzuki K：“双相情感障碍患者血小板中星形孢菌素的存在改变了 5-HT 诱导的钙反应”神经精神药物学。

Darier病遺伝子と気分障害の病態研究

达里尔病基因与情绪障碍的病理学研究

• 发表时间: 2003
• 期刊: 分子精神医学 3
• 作者: Okamoto H;Mizuno K;Horio T;T.Hirobe.;Kusumi I et al.;Okamoto Hiroyuki et al.;久住 一郎
• 通讯作者: 久住 一郎

Kakiuchi C: "Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder"Nature Genetics. 35. 171-175 (2003)

Kakiuchi C：“XBP1 反馈调节受损是双相情感障碍的遗传风险因素”《自然遗传学》。

Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder

• DOI: 10.1038/ng1235
• 发表时间: 2003-10-01
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Kakiuchi, C;Iwamoto, K;Kato, T
• 通讯作者: Kato, T