中枢神经系统中的大多数兴奋型神经传输（允许神经元彼此沟通的事件）是由离子型谷氨酸盐受体调控的，这些受体通过打开结合谷氨酸盐上的一个跨膜离子通道发挥作用。过去人们对它们的总体结构知之甚少，但现在Eric Gouaux及其同事报告了结合到一个竞争性拮抗剂上的对AMPA敏感的亚型“大鼠GluA2受体”的X-射线晶体结构。
该受体（如封面图片所示）具有一个出乎意料的对称性和亚单元排列：总体上为双重对称，细胞外区域按局部二聚体对的形式来组织。离子通道区域表现出四重对称。这种结构（是根据来自定点诱变实验的数据获得的）表明，对NMDA敏感的受体GluN1 和 GluN2A在总体结构上与GluA2相似。从这些结构可以推断出非竞争性拮抗剂和孔阻断分子对离子通道的激发、脱敏和抑制机制。（生物谷Bioon.com）
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生物谷推荐原始出处：
Nature 462, 745-756 (10 December 2009) | doi:10.1038/nature08624
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor
Alexander I. Sobolevsky1, Michael P. Rosconi1,3 & Eric Gouaux1,2
1 Vollum Institute,
2 Howard Hughes Medical Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA
3 Present address: Regeneron Pharmaceuticals, Inc., Protein Chemistry Sciences, 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA.
Correspondence to: Eric Gouaux1,2 Correspondence and requests for materials should be addressed to E.G.
Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6?? resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.
