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AMPA 受体的开放闸门形成了一个钙结合位点，对于调节离子转运至关重要。

The open gate of the AMPA receptor forms a Ca binding site critical in regulating ion transport.

机构信息

Department of Molecular Physiology and Biophysics, Vanderbilt University, School of Medicine, Nashville, TN, USA.

Center for Structural Biology, Vanderbilt University, School of Medicine, Nashville, TN, USA.

出版信息

Nat Struct Mol Biol. 2024 Apr;31(4):688-700. doi: 10.1038/s41594-024-01228-3. Epub 2024 Feb 26.

DOI:10.1038/s41594-024-01228-3
PMID:38409505
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11536930/
Abstract

Alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are cation-selective ion channels that mediate most fast excitatory neurotransmission in the brain. Although their gating mechanism has been studied extensively, understanding how cations traverse the pore has remained elusive. Here we investigated putative ion and water densities in the open pore of Ca-permeable AMPARs (rat GRIA2 flip-Q isoform) at 2.3-2.6 Å resolution. We show that the ion permeation pathway attains an extracellular Ca binding site (site-G) when the channel gate moves into the open configuration. Site-G is highly selective for Ca over Na, favoring the movement of Ca into the selectivity filter of the pore. Seizure-related N619K mutation, adjacent to site-G, promotes channel opening but attenuates Ca binding and thus diminishes Ca permeability. Our work identifies the importance of site-G, which coordinates with the Q/R site of the selectivity filter to ensure the preferential transport of Ca through the channel pore.

摘要

α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 (AMPARs) 是阳离子选择性离子通道，介导大脑中大多数快速兴奋性神经递质传递。尽管它们的门控机制已被广泛研究，但阳离子如何穿过孔道仍难以捉摸。在这里，我们在 2.3-2.6 Å 分辨率下研究了可渗透钙的 AMPAR（大鼠 GRIA2 flip-Q 异构体）开放孔道中可能的离子和水密度。我们表明，当通道门移动到开放构象时，离子渗透途径达到一个胞外 Ca 结合位点（位点-G）。位点-G 对 Ca 的选择性高于 Na，有利于 Ca 进入孔道的选择性过滤器。与位点-G 相邻的与癫痫发作相关的 N619K 突变促进通道打开，但会减弱 Ca 结合，从而降低 Ca 通透性。我们的工作确定了位点-G 的重要性，它与选择性过滤器的 Q/R 位点协同作用，以确保 Ca 通过通道孔道的优先转运。

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