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CAPS 1和CAPS 2与Arf 4/5相互作用，Arf 4/5可能参与trans-Golgi网络（TGN）中的致密核心囊泡（DCV）运输。Dex 3（exon 3缺失）是一种罕见的CAPS 2选择性剪接变异体，在部分自闭症患者中表达增加。我们产生了dex 3表达小鼠，并验证了轴突dex 3定位的损伤，有助于减少BDNF从轴突释放，从而导致异常突触。dex 3小鼠也表现出社交和焦虑行为的缺陷，这表明dex 3与自闭症相关的大脑发育和行为可能存在关联。尽管CAPS 1调节胰岛素分泌，但由于CAPS 1 KO小鼠的新生儿死亡，其在脑中的功能基本上是未知的。我们产生了CAPS 1条件性敲除小鼠，并表明CAPS 1的缺失破坏了TGN-DCV通路和BDNF的释放，这可能与糖尿病和共病抑郁症的潜在机制有关。

项目成果

Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses.

• DOI: 10.1186/1756-6606-6-6
• 发表时间: 2013-01-28
• 期刊: Molecular brain
• 影响因子: 3.6
• 作者: Tanaka M;Shih PY;Gomi H;Yoshida T;Nakai J;Ando R;Furuichi T;Mikoshiba K;Semyanov A;Itohara S
• 通讯作者: Itohara S

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

Interaction between very-KIND RasGEF and MAP2, and its role in dendrite growth : structure and function of the second kinase non-catalytic C-lobe domain.

very-KIND RasGEF 和 MAP2 之间的相互作用及其在树突生长中的作用：第二个激酶非催化 C 叶结构域的结构和功能。

• 发表时间: 2011
• 期刊: FEBS J 278
• 作者: Huang J.;Furuya A.;Hayashi K.;Furuichi T.
• 通讯作者: Furuichi T.