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    题名: A new perspective on betaine: Targeting the glycine binding site of the NMDA receptor
    作者: 詹銘煥
    Chan, Ming-Huan;Chang, Wei-Tang;Lee, Mei-Yi;Wang, Ya-Jean;Huang, Wei-Cheng;Hsiesh, Chung-Ping;Tung, Chun-Wei;Chan, Ming-Huan;Chen, Hwei-Hsien
    贡献者: 神科所
    关键词: Calcium image;Glutamate;Glycine;GluN2A;GluN2B;GluN2C
    日期: 2025-12
    上传时间: 2025-11-13 10:59:08 (UTC+8)
    摘要: Betaine, a methylated glycine derivative, shows promise in treating neuropsychiatric and neurological disorders, but its mechanisms remain unclear. This study investigates betaine’s concentration-dependent effects on NMDA receptor-mediated excitatory field potentials (EFPs) in mouse medial prefrontal cortex slices and calcium influx in cultured cortical neurons. We further assessed subtype specificity using HEK293 cells stably expressing GluN1/GluN2A, GluN1/GluN2B, or GluN1/GluN2C NMDA receptor subtypes, measuring calcium flux and single-channel activity. In cortical slices, betaine alone did not alter EFPs but, when co-applied with glutamate, significantly increased EFP frequency and amplitude. Conversely, co-application with glutamate and glycine markedly reduced EFPs. Similarly, in cultured cortical neurons, betaine enhanced NMDA receptor-dependent calcium influx with glutamate alone but attenuated it when both glutamate and glycine were present. In HEK293 cells, betaine exhibited dual modulatory effects on NMDA receptor-mediated calcium influx, varying with GluN2 subtype and glutamate/glycine concentrations. Cell-attached patch-clamp recordings confirmed that betaine with glutamate induced NMDA receptor currents, which were reduced by glycine co-application. Molecular docking and dynamics simulations proposed that betaine binds effectively to the glycine-binding site on the GluN1 subunit, with stable interactions. These findings identify betaine as a context-dependent modulator of NMDA receptors via its interaction with the glycine-binding site, offering a novel mechanism that may underlie its therapeutic potential in disorders involving NMDA receptor dysfunction.
    關聯: Biochemical Pharmacology, No.242, No.3, 117213
    数据类型: article
    DOI 連結: https://doi.org/10.1016/j.bcp.2025.117213
    DOI: 10.1016/j.bcp.2025.117213
    显示于类别:[神經科學研究所] 期刊論文

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