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Modulation of synaptic signal transduction by cross-talk between Ca2+- and Rho-dependent signaling.

通过 Ca2 和 Rho 依赖性信号传导之间的串扰来调节突触信号转导。

基本信息

批准号：
11670115
负责人：
BITO Haruhiko
金额：
$ 2.3万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670115/
关键词：
CREB CaMKIV Rho Ca2+ROCK Cerebellar granule cells Citron Cupidin PSD-95 NMDA受容体視床 Homer 電位依存症カルシウムチャンネル

项目摘要

Signaling from synapse to nucleus triggers activation of nuclear CaMKIV in a synpatic activity-dependent manner. We previously showed that Ca2+-influx channels that mediate this response are localized to the synapse. However the molecular and ctoskeletal mechanisms by which this is achieved remains unsolved. Here, we considered the possibility that molecules involved in Rho small GTPase signaling might contribute to such a process. By investigating a potential physical link between components of synaptic activity-dependent Ca2+-mobilization mechanisms and components of Rho-mediated signaling, we discovered :1) the presence of a novel synaptic protein complex consisting of a Rho-effector, Citron-N, and PSD- 95/NMDA-receptor subunits ;2) an association between Cupidin/Homer2a/Vesl2 and Rho-actin cytoskeleton system. These findings represent the first molecular indication that Rho signaling may truly participate in organizing a synaptic Ca2+-mobilization complex, either at the level of NMDA receptors or the intracellular Ca2+ stores. Furthermore, during the course of these studies, we established that :3) Rho/ROCK signaling functions as a gate critical for the negative regulation of axonal outgrowth during cerebellar granule cell development ;4) a novel proteolytic cleavage of CaMKIV may represent a novel mechanism to control the amount of activation of the CaMKIV/CREB pathway ; such regulatory process may be implicated in the maintainance of survival in cerebellar granule cells in culture.

从突触到细胞核的信号传导以突触活性依赖的方式触发细胞核CaMKIV的激活。我们先前表明，介导这种反应的Ca 2+内流通道定位于突触。然而，实现这一点的分子和细胞骨架机制仍然没有解决。在这里，我们考虑了参与Rho小GT3信号传导的分子可能有助于这样一个过程的可能性。通过研究突触活动依赖性Ca 2+动员机制的成分与Rho介导的信号传导成分之间的潜在物理联系，我们发现：1）存在一种新型突触蛋白复合物，该复合物由Rho效应器、Citron-N和PSD- 95/NMDA受体亚基组成;2）Cupidin/Homer 2a/Vesl 2与Rho-肌动蛋白细胞骨架系统之间的关联。这些发现代表了第一个分子迹象表明，Rho信号可能真正参与组织突触Ca 2+动员复合物，无论是在NMDA受体或细胞内Ca 2+商店的水平。此外，在这些研究的过程中，我们建立了：3）Rho/ROCK信号作为一个门的功能，在小脑颗粒细胞发育过程中的轴突生长的负调控的关键;4）一种新的蛋白水解切割的CaMKIV可能代表一种新的机制，以控制激活的CaMKIV/CREB通路的量;这种调节过程可能涉及在小脑颗粒细胞的存活率在培养中的死亡。