近日，英国剑桥医学研究委员会分子生物学实验室神经生物学部教授Ingo H. Greger及其团队报道了谷氨酸A3 AMPA受体的结构、动力学和生物发生。该项研究成果发表在2025年7月1日出版的《自然》上。

该研究组展示了CP GluA3同质体的低温电镜结构，它与其他AMPARs有很大的不同。GluA3细胞外结构域层（NTD和LBD）在整个门控状态中紧密耦合，创造了以前未见过的影响信号传导并包含其人类疾病突变的界面。该结构的核心是NTD二聚体界面中两个精氨酸残基（Arg163）之间的堆叠相互作用，捕获独特的NTD二聚体构象，使其能够与LBD紧密接触。Arg163堆叠的断裂不仅改变了GluA3胞外区域的结构和动力学，而且增加了受体的运输，增加了GluA3异构体在突触上的表达。小组进一步表明，哺乳动物特异性的GluA3转运检查点决定了LBD层的构象稳定性。因此，特定的设计特征定义了GluA3的通讯和生物发生，为询问这种易患病的谷氨酸受体提供了一个框架。

研究人员表示，AMPA型谷氨酸受体（AMPARs）介导大脑中大部分兴奋性神经传递。它们的核心亚基GluA1-4和~20个辅助亚基组合而成，其分子多样性以脑回路特定的方式调节信息传递和存储。GluA3是一种与疾病密切相关的亚型，在感觉突触中作为一种快速传递的Ca²⁺渗透性（CP） AMPAR，在皮质突触中作为一种Ca²⁺不渗透性（CI）受体。

附：英文原文

Title: Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors

Author: Pokharna, Aditya, Stockwell, Imogen, Ivica, Josip, Singh, Bishal, Schwab, Johannes, Vega-Gutirrez, Carlos, Herguedas, Beatriz, Cais, Ondrej, Krieger, James M., Greger, Ingo H.

Issue&Volume: 2025-07-01

Abstract: AMPA-type glutamate receptors (AMPARs) mediate the majority of excitatory neurotransmission in the brain1. Assembled from combinations of four core subunits, GluA1-4, and ~20 auxiliary subunits, their molecular diversity tunes information transfer and storage in a brain circuit-specific manner. GluA3, a subtype strongly associated with disease2, functions as both a fast transmitting Ca2+-permeable (CP) AMPAR at sensory synapses3, and as a Ca2+-impermeable (CI) receptor at cortical synapses4,5. Here, we present cryo-EM structures of the CP GluA3 homomer, which substantially diverge from other AMPARs. The GluA3 extracellular domain tiers (NTD and LBD) are closely coupled throughout gating states, creating previously unseen interfaces that impact signalling and harbour human disease mutations. Central to this architecture is a stacking interaction between two arginine residues (Arg163) in the NTD dimer interface, trapping a unique NTD dimer conformation that enables close contacts with the LBD. Rupture of the Arg163 stack not only alters the structure and dynamics of the GluA3 extracellular region, but also increases receptor trafficking, and the expression of GluA3 heteromers at the synapse. We further show that a mammalian-specific GluA3 trafficking checkpoint determines conformational stability of the LBD tier. Hence, specific design features define communication and biogenesis of GluA3, offering a framework to interrogate this disease-prone glutamate receptor.

DOI: 10.1038/s41586-025-09325-z

Source: https://www.nature.com/articles/s41586-025-09325-z