Study on the molecular mechanisms underlying CAPS-mediated exocytosis of dense-core vesicles containing BDNF and catecholamine

CAPS介导的BDNF和儿茶酚胺致密核囊泡胞吐作用的分子机制研究

• 批准号: 23300137
• 负责人: FURUICHI Teiichi
• 金额: $ 12.9万
• 依托单位: Tokyo University of Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23300137/
• 关键词: CAPS1; CAPS2; 有芯小胞; BDNF; トランスゴルジ網; 自閉症; CAPS2-dex3; NT-3; 社会行動; Cadps2; Arf4/5; ゴルジ体; 発達障害

We showed that CAPS1 and CAPS2 interacts with Arf4/5, which is possibly involved in dense-core vesicle (DCV) trafficking in the trans-Golgi network (TGN). Dex3 (deletion of exon3) is a rare alternative splicing CAPS2 variant which was identified to be increased in some of patients with autism. We generated a dex3-expressing mice and verified an impairment in axonal dex3 localization, contributing to a reduction in BDNF release from axons and thereby resulting in abnormal synapses. Dex3 mice also showed deficits in social and anxiety behaviors, suggesting a possible association of dex3 with brain development and behavior related to autism. Although CAPS1 regulates insulin secretion, its function in the brain is essentially unknown because of neonatal death of CAPS1 KO mice. We generated CAPS1 conditional knockout mice and suggested that loss of CAPS1 disrupts the TGN-DCV pathway and BDNF release, which may be associated with a mechanism underlying diabetes and comorbid depression.

我们表明，CAPS1和CAPS2与ARF4/5相互作用，ARF4/5可能与反式高尔基网络（TGN）中的密集核囊泡（DCV）交通有关。 DEX3（Exon3的缺失）是一种罕见的替代剪接CAPS2变体，在某些自闭症患者中被确定为增加。我们产生了表达DEX3的小鼠，并验证了轴突DEX3定位的损伤，导致轴突从BDNF释放减少，从而导致异常突触。 DEX3小鼠还显示出社会和焦虑行为的缺陷，这表明DEX3可能与大脑发育和与自闭症有关的行为有关联。尽管CAPS1调节胰岛素分泌，但由于CAPS1 KO小鼠的新生儿死亡，其在大脑中的功能本质上是未知的。我们生成了有条件的敲除小鼠的CAPS1，并建议CAPS1的损失破坏TGN-DCV途径和BDNF释放，这可能与糖尿病和合并抑郁症的机制有关。

项目成果

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

• DOI: 10.1073/pnas.1012220108
• 发表时间: 2011-01-04
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Shinoda, Yo;Sadakata, Tetsushi;Furuichi, Teiichi
• 通讯作者: Furuichi, Teiichi

Enhanced secretion of BDNF by CAPS2 is critical for proper brain development and behavior

CAPS2 增强 BDNF 的分泌对于大脑的正常发育和行为至关重要

• 发表时间: 2011
• 作者: Furuichi T;Sadakata T and Shinoda Y
• 通讯作者: Sadakata T and Shinoda Y

BDNFによって増強される興奮性シナプス小胞分泌のメカニズム

BDNF增强兴奋性突触小泡分泌的机制

• 发表时间: 2013
• 作者: 土井樹;古市貞一;篠田陽;Camin Dean
• 通讯作者: Camin Dean

自閉症の発症要因と動物モデル

自闭症发病因素和动物模型

• 发表时间: 2012
• 作者: 篠田陽;定方哲史;三島百合子;古市貞一
• 通讯作者: 古市貞一

マウスドーパミン作動性神経の初代培養系における大型有芯小胞からのドーパミン分泌とCAPS2の関係

小鼠多巴胺能神经元原代培养体系中大核心囊泡分泌多巴胺与CAPS2的关系

• 发表时间: 2013
• 作者: 井口大壽;小林翔太;定方哲史;篠田陽;古市貞一
• 通讯作者: 古市貞一