National Natural Science Foundation of China (NSFC)
31771115
中国
National Natural Science Foundation of China (NSFC)
31671049
中国
National Natural Science Foundation of China (NSFC)
81030065
中国
Chinese Academy of Sciences
XDB32020000
中国
Chinese Academy of Sciences
XDA12040214
中国
Chinese Academy of Sciences
XDA12040220
中国
National Natural Science Foundation of China (NSFC)
81803828
中国
Chinese Academy of Sciences
2019280
中国
National Natural Science Foundation of China (NSFC)
32221003
中国
引用
ジャーナル: Sci Adv / 年: 2025 タイトル: An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons. 著者: Jilin Zhang / Jinjin Duan / Wei Li / Xian Wang / Shimin Ren / Luyu Ye / Fang Liu / Xiaoting Tian / Yang Xie / Yiming Huang / Yidi Sun / Nan Song / Tianyu Li / Xiang Cai / Zhiqiang Liu / Hu ...著者: Jilin Zhang / Jinjin Duan / Wei Li / Xian Wang / Shimin Ren / Luyu Ye / Fang Liu / Xiaoting Tian / Yang Xie / Yiming Huang / Yidi Sun / Nan Song / Tianyu Li / Xiang Cai / Zhiqiang Liu / Hu Zhou / Chenggang Huang / Yang Li / Shujia Zhu / Fei Guo / 要旨: -methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine ...-methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine their pharmacological properties. Few compounds selectively targeting GluN2 subunits with antidepressant effects have been identified. Here, we present YY-23, a compound that selectively inhibits GluN2C- or GluN2D-containing NMDARs. Cryo-EM analysis revealed that YY-23 binds to the transmembrane domain of the GluN2D subunit. YY-23 primarily affects GluN2D-containing NMDARs on GABAergic interneurons in the prefrontal cortex, suppressing GABAergic neurotransmission and enhancing excitatory transmission. Behavioral assays demonstrate YY-23's rapid antidepressant effects in both stress-naïve and stress-exposed models, which are lost in mice with global or selective knockout of the gene in parvalbumin-positive interneurons. These findings highlight GluN2D-containing NMDARs on GABAergic interneurons as potential depression treatment targets.
材質: nanodisc 詳細: The protein sample of N-methyl-D-aspartate receptors was reconstructed into artificial nanodiscs composed by soya bean lecithin and MSP1E3D1 protein.