Differential contribution of individual receptor subunits of N-methyl-d-aspartate to ischemic neuronal damage.

N-甲基-d-天冬氨酸单个受体亚基对缺血性神经元损伤的不同贡献。

• 批准号: 21591081
• 负责人: SASAKI Tsutomu
• 金额: $ 2.16万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591081/
• 关键词: NMDA受容体; NR2A; NR2B; TORC1/ CRTC1; SIK2; CREB; NDMA受容体; サブタイプ; α7 nchR; 脳虚血; TORC1; NDMA受容; 虚血耐性

The cAMP responsive element-binding protein(CREB) functions in a broad array of biological and pathophysiological processes. We found that salt-inducible kinase 2(SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation(OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1(TORC1), resulting in the activation of CREB and its downstream gene targets. Ca(2+)/ calmodulin-dependent protein kinase I/ IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2(-/-) mice, and ischemic neuronal injury was significantly reduced in the brains of sik2(-/-) mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/ IV, and regulates CREB via TORC1.

cAMP反应元件结合蛋白（CREB）在广泛的生物学和病理生理过程中发挥作用。我们发现，盐诱导激酶2（SIK 2）在神经元中大量表达，并抑制CREB介导的基因表达后，氧-葡萄糖剥夺（OGD）。OGD诱导SIK 2蛋白的降解，同时伴有CREB特异性调节CREB活性的辅激活因子转导子1（TORC 1）的去磷酸化，导致CREB及其下游基因靶点的激活。Ca（2+）/钙调素依赖性蛋白激酶I/ IV能够在Thr 484磷酸化SIK 2，导致SIK 2在皮质神经元中降解。从sik 2（-/-）小鼠分离的神经元中，OGD后的神经元存活率显著增加，并且在经受短暂局灶性缺血的sik 2（-/-）小鼠的脑中，缺血性神经元损伤显著减少。这些发现表明，SIK 2在神经元存活中起着关键作用，由CaMK I/ IV调节，并通过TORC 1调节CREB。

项目成果

脳虚血時におけるSIK-TORC1経路の意義

SIK-TORC1通路在脑缺血过程中的意义

• 发表时间: 2011
• 作者: Watanabe A;Matsushita T;Doi H;Matsuoka T;Shigeto H;Isobe N;Kawano Y;Tobimatsu S;Kira J;佐々木勉
• 通讯作者: 佐々木勉

神経細胞におけるニコチンによるCREB調節機構の検討

尼古丁对神经元CREB调节机制的研究

• 发表时间: 2011
• 作者: Seki T;Takahashi H;Yamamoto K;Ogawa K;Onji T;Adachi N;Tanaka S;Hide I;Saito N;Sakai N.;佐々木勉
• 通讯作者: 佐々木勉

Cilostazol, Not Aspirin, Reduces Ischemic Brain Injury via Endothelial Protection in Spontaneously Hypertensive Rats

• DOI: 10.1161/strokeaha.110.609834
• 发表时间: 2011-09-01
• 期刊: STROKE
• 影响因子: 8.3
• 作者: Oyama, Naoki;Yagita, Yoshiki;Kitagawa, Kazuo
• 通讯作者: Kitagawa, Kazuo

SIK2 Is a Key Regulator for Neuronal Survival after Ischemia via TORC1-CREB

• DOI: 10.1016/j.neuron.2010.12.004
• 发表时间: 2011-01-13
• 期刊: NEURON
• 影响因子: 16.2
• 作者: Sasaki, Tsutomu;Takemori, Hiroshi;Kitagawa, Kazuo
• 通讯作者: Kitagawa, Kazuo

Implication of TORC1-CREB cascade in neuronal survival

TORC1-CREB级联对神经元存活的影响

• 发表时间: 2011
• 作者: Miyazaki K;Nagai M;Ohta Y;Morimoto N;Kurata T;Murakami T;Takehisa Y;Ikeda Y;Kamiya T;Abe K;Sasaki T et al.
• 通讯作者: Sasaki T et al.