Regulation of spine morphology by RICS-dependent Cdc42 signaling

Research Project

Project/Area Number	17K07104
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Neurochemistry/Neuropharmacology
Research Institution	The University of Tokyo
Principal Investigator	Nakamura Tsutomu 東京大学, 定量生命科学研究所, 客員准教授 (30302798)
Project Period (FY)	2017-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000) Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000) Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords	シグナル伝達 / シナプス / スパイン / グルタミン酸受容体 / CaMKII / Cdc42 / アクチン / RICS / 神経科学 / 脳・神経 / 脳神経疾患
Outline of Final Research Achievements	We previously identified RICS, which is localized in the postsynaptic density and forms a complex with glutamate receptors and PSD-95. RICS functions as a Cdc42GAP that regulates the downstream Cdc42-mediated signaling. We hypothesized that RICS regulates the Cdc42-PAK-LIMK-Cofilin signaling pathway and tested the hypothesis in this study. We conducted in vitro experiments using primary cultured neurons derived from wild-type and RICS KO mice, inhibitors, and dominant negative mutants. We found that stimulation of neurons with glutamate leads to the activation of PAK, LIMK, and Cofilin in the CaMKII- or RICS-dependent manner. This finding suggests that glutamate, an excitatory neurotransmitter, activates Cdc42-PAK-LIMK-Cofilin signaling through glutamate receptors, CaMKII, and RICS.
Academic Significance and Societal Importance of the Research Achievements	高次脳機能の重要な細胞基盤として、グルタミン酸の興奮性刺激に依存したスパイン形態やシナプス伝達効率の制御が考えられている。Cofilinはスパイン骨格を構成するアクチン線維の動態を調節するタンパク質なので、上記のシグナル伝達経路によるアクチン動態の調節が、スパイン形態やシナプス伝達効率の制御に関与している可能性が示唆された。