近日，中国科学院生物物理研究所赵岩小组开发出小脑天然AMPA受体的组装和门控机制。相关论文发表在2026年3月16日出版的《细胞研究》杂志上。

研究团队生成了一种高特异性的GluA4抗体。利用该抗体结合特异性识别GluA1和GluA2的抗体，课题组纯化了天然AMPARs，并测定了小脑中钙不渗透和钙渗透的天然AMPARs的亚基组成。同时含有GluA1和GluA4的离体小脑AMPARs具有钙透性，其中GluA4主要占据B/D位置，GluA1占据A/C位置，复合物主要与cornichon 3 （CNIH3）相关。

小组确定了该复合物在不同功能状态下的结构，包括静息状态、活性状态和脱敏状态，并表征了其活性背后的构象转变。在脱敏过程中，受体采用配体结合域层的伪4重结构，这可能对其功能特性很重要。本研究为AMPARs在小脑中的亚基组成提供了蓝图，并阐明了钙渗透性天然AMPARA1A4-CNIH3复合物的门控机制，为AMPARs介导的小脑突触传递提供了重要的见解。

研究人员表示，AMPA受体介导了整个中枢神经系统的大部分快速兴奋性突触传递。钙渗透性AMPARs和含有GluA4的受体对小脑功能至关重要，如运动学习、联想记忆、听觉加工和突触可塑性。与已知的海马和皮层中主要含有GluA2的AMPARs相比，小脑AMPARs含有更高比例的GluA4，但对其了解甚少。

附：英文原文

Title: Assembly and gating mechanism of native AMPA receptors from the cerebellum

Author: Li, Xiaojing, Li, Renjie, Wei, Yiqing, Chen, Jiexin, Zhao, Jiaojiao, Zhao, Jun, Wang, Wei, Li, Na, Wang, Lili, Hu, Tuo, Dong, Yanli, Zhu, Yongping, Wei, Chao, Li, Long, Zhang, Wei, Huang, Zhuo, Zhao, Yan

Issue&Volume: 2026-03-16

Abstract: AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission throughout the central nervous system. Calcium-permeable AMPARs and GluA4-containing receptors are critical for cerebellar functions, such as motor learning, associative memory, auditory processing, and synaptic plasticity. In contrast to the well-characterized, predominantly GluA2-containing AMPARs of the hippocampus and cortex, cerebellar AMPARs contain a higher proportion of GluA4 and remain poorly understood. Here, we generated a highly GluA4-specific antibody. Using this antibody in combination with antibodies specifically recognizing GluA1 and GluA2, we purified native AMPARs and determined the subunit compositions of both calcium-impermeable and calcium-permeable native AMPARs in the cerebellum. The isolated cerebellar AMPARs that contained both GluA1 and GluA4 were calcium-permeable, with GluA4 occupying mainly the B/D positions, GluA1 occupying the A/C positions, and the complex associated primarily with cornichon 3 (CNIH3). We determined the structures of the complex in distinct functional states, including the resting, active, and desensitized states, and characterized the conformational transitions that underlie its activity. During desensitization, the receptor adopts a pseudo-4-fold configuration of the ligand-binding domain layer, which may be important for its functional properties. This study provides a blueprint for the subunit compositions of AMPARs in the cerebellum and clarifies the gating mechanism of the calcium-permeable native AMPARA1A4–CNIH3 complex, providing significant insight into AMPAR-mediated synaptic transmission in the cerebellum.

DOI: 10.1038/s41422-026-01234-8

Source: https://www.nature.com/articles/s41422-026-01234-8