船橋 靖広, Ahammad Rijwan Uddin, 張 心健, Emran Hossen, Faruk Md. Omar, 王 緩緩, 呉 敏華, 許 伊凡, 坪井 大輔, 西岡 朋生, 黒田 啓介, 天野 睦紀, 崎村 建司, 内野 茂夫, 山田 清文, 永井 拓, 貝淵 弘三
日本薬理学会年会要旨集 96 2-B-P-109 2022年
Glutamate induces Ca2+ influx in neurons through NMDA receptors (NMDARs) and activates Ca2+-dependent protein kinases, including CaMKII, which play critical roles in synaptic plasticity and learning. However, how these kinases regulate synaptic plasticity and learning remains largely unknown. Here, we performed phosphoproteomics and identified 160 proteins including ArhGEF2 whose phosphorylation were promoted by NMDA. CaMKII phosphorylated ArhGEF2 and stimulated its RhoGEF activity. Aversive stimuli induced CaMKII-mediated ArhGEF2 phosphorylation and Rho-kinase/ROCK activation in the nucleus accumbens (NAc). Inhibition of Rho-kinase in the NAc attenuated aversive learning. We also screened Rho-kinase substrates and identified 221 proteins including Shank3 which links actin filaments with NMDARs and AMPA receptors via Dlgap3. The Rho-kinase-mediated phosphorylation of Shank3 increased its interaction with Dlgap3. Manipulation of Shank3 in the NAc regulated dendritic spine formation and aversive learning in a phosphorylation-dependent manner. These results demonstrate that NMDA activates the CaMKII-ArhGEF2-Rho-kinase pathway to induce Shank3 phosphorylation for aversive learning.