约翰霍普金斯大学医学院Edward C. Twomey课题组宣布他们揭示了δ型谷氨酸受体是配体门控离子通道。相关论文于2025年9月16日发表于国际顶尖学术期刊《自然》杂志上。

课题组将GluDs定义为配体门控离子通道，通过纯化人GluD2（hGluD2）并通过低温电子显微镜（cryoEM）和双层记录直接表征其结构和功能，在细胞环境中受到严格调节。研究人员发现hGluD2被D-丝氨酸和γ-氨基丁酸（GABA）激活，在生理温度下激活增强。该课题组发现hGluD2包含一个离子通道直接偶联到蛤壳状配体结合域（LBDs）， LBDs由离子通道上方的氨基末端结构域（ATD）协调。配体结合通过不对称机制触发通道打开，LBD中的小脑共济失调点突变重新排列受体结构并诱导泄漏电流。他们的研究结果表明，GluD2具有配体门控离子通道的内在生物物理特性，调和了先前相互矛盾的观察结果，为理解其细胞调控和开发针对GluD2的治疗建立了框架。

据悉，δ型离子型谷氨酸受体（iGluRs）是iGluR配体门控离子通道家族的成员，但其功能仍是谜。尽管GluDs在大脑中广泛表达，在突触组织中发挥关键作用，并携带与疾病相关的突变，但由于电流尚未直接观察到，它们是否保留iGluR样通道功能仍存在争议。

附：英文原文

Title: Delta-type glutamate receptors are ligand-gated ion channels

Author: Wang, Haobo, Ahmed, Fairine, Khau, Jeffrey, Mondal, Anish Kumar, Twomey, Edward C.

Issue&Volume: 2025-09-16

Abstract: Delta-type ionotropic glutamate receptors (iGluRs), or GluDs, are members of the iGluR ligand-gated ion channel family, yet their function remains enigmatic1. Although GluDs are widely expressed in the brain, play key roles in synaptic organization, and harbor disease-linked mutations, whether they retain iGluR-like channel function is debated as currents have not been directly observed2,3. Here, we define GluDs as ligand-gated ion channels that are tightly regulated in cellular contexts by purifying human GluD2 (hGluD2) and directly characterizing its structure and function using cryo-electron microscopy (cryoEM) and bilayer recordings. We show that hGluD2 is activated by D-serine and γ-aminobutyric acid (GABA), with augmented activation at physiological temperatures. We reveal that hGluD2 contains an ion channel directly coupled to clamshell-like ligand-binding domains (LBDs), which are coordinated by the amino terminal domain (ATD) above the ion channel. Ligand binding triggers channel opening via an asymmetric mechanism, and a cerebellar ataxia point mutation in the LBD rearranges the receptor architecture and induces leak currents. Our findings demonstrate that GluDs possess the intrinsic biophysical properties of ligand-gated ion channels, reconciling prior conflicting observations to establish a framework for understanding their cellular regulation and for developing therapies targeting GluD2.

DOI: 10.1038/s41586-025-09610-x

Source: https://www.nature.com/articles/s41586-025-09610-x