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.

我们发现 CAPS1 和 CAPS2 与 Arf4/5 相互作用，Arf4/5 可能参与跨高尔基体网络 (TGN) 中的致密核心囊泡 (DCV) 运输。 Dex3（外显子 3 缺失）是一种罕见的选择性剪接 CAPS2 变体，已发现该变体在一些自闭症患者中增加。我们培育了一只表达 dex3 的小鼠，并验证了轴突 dex3 定位的损伤，导致轴突释放 BDNF 减少，从而导致突触异常。 Dex3小鼠还表现出社交和焦虑行为缺陷，这表明dex3可能与大脑发育和自闭症相关行为有关。尽管CAPS1调节胰岛素分泌，但由于CAPS1 KO小鼠的新生儿死亡，其在大脑中的功能基本上是未知的。我们生成了 CAPS1 条件敲除小鼠，并表明 CAPS1 的缺失会破坏 TGN-DCV 通路和 BDNF 释放，这可能与糖尿病和共病抑郁症的潜在机制有关。

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

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

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

刺激の違いによるBDNF放出動態の比較とCAPS2活性に関わるCa2+チャネルの特定

不同刺激下 BDNF 释放动态的比较以及参与 CAPS2 活性的 Ca2+ 通道的鉴定

• 发表时间: 2013
• 作者: 中川直紀;篠田陽;古市貞一;松尾誠
• 通讯作者: 松尾誠