加拿大麦吉尔大学Derek Bowie研究团队报道了含GluA2的AMPA受体形成连续的Ca²⁺可渗透通道。相关论文于2025年3月19日发表在《自然》杂志上。

这里研究组展示的不是这种情况。与传统的理解相反，含有GluA2的AMPARs形成了一个连续的多胺不敏感离子通道，具有不同程度的Ca²⁺通透性。它们运输Ca²⁺的能力是由AMPAR四聚体的亚基组成以及跨膜AMPAR调节蛋白和角蛋白辅助亚基的空间取向决定的。Ca²⁺通过对接到细胞外结合位点穿过离子传导途径，帮助将二价离子漏斗到孔选择性过滤器中。然而，Ca²⁺通透性的动态范围是由于辅助亚基主要修饰选择性过滤器而产生的。综上所述，他们的工作提出了AMPAR在哺乳动物大脑中Ca²⁺信号传导中的更广泛作用，并为错义突变的致病性质提供了机制见解。

据了解，哺乳动物脑内的快速兴奋性神经传递是由阳离子选择性AMPA （α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）受体介导的。AMPAR在Hebbian可塑性和谷氨酸突触稳态的学习和记忆机制中起着至关重要的作用，最近的研究表明AMPAR错义突变可能导致自闭症和智力障碍。基于GluA2亚基的内嵌或外嵌，AMPARs被分为两个功能不同的四聚体组件，GluA2亚基通过RNA编辑决定Ca²⁺的渗透性。含有GluA2的AMPARs在中枢神经系统中最丰富，被认为是Ca²⁺不渗透的。

附：英文原文

Title: GluA2-containing AMPA receptors form a continuum of Ca2+-permeable channels

Author: Miguez-Cabello, Federico, Wang, Xin-tong, Yan, Yuhao, Brake, Niklas, Alexander, Ryan P. D., Perozzo, Amanda M., Khadra, Anmar, Bowie, Derek

Issue&Volume: 2025-03-19

Abstract: Fast excitatory neurotransmission in the mammalian brain is mediated by cation-selective AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors (AMPARs)1. AMPARs are critical for the learning and memory mechanisms of Hebbian plasticity2 and glutamatergic synapse homeostasis3, with recent work establishing that AMPAR missense mutations can cause autism and intellectual disability4,5,6,7. AMPARs have been grouped into two functionally distinct tetrameric assemblies based on the inclusion or exclusion of the GluA2 subunit that determines Ca2+ permeability through RNA editing8,9. GluA2-containing AMPARs are the most abundant in the central nervous system and considered to be Ca2+ impermeable10. Here we show this is not the case. Contrary to conventional understanding, GluA2-containing AMPARs form a continuum of polyamine-insensitive ion channels with varying degrees of Ca2+ permeability. Their ability to transport Ca2+ is shaped by the subunit composition of AMPAR tetramers as well as the spatial orientation of transmembrane AMPAR regulatory proteins and cornichon auxiliary subunits. Ca2+ crosses the ion-conduction pathway by docking to an extracellular binding site that helps funnel divalent ions into the pore selectivity filter. The dynamic range in Ca2+ permeability, however, arises because auxiliary subunits primarily modify the selectivity filter. Taken together, our work proposes a broader role for AMPARs in Ca2+ signalling in the mammalian brain and offers mechanistic insight into the pathogenic nature of missense mutations.

DOI: 10.1038/s41586-025-08736-2

Source: https://www.nature.com/articles/s41586-025-08736-2