中樞神經(jīng)系統(tǒng)中的大多數(shù)興奮型神經(jīng)傳輸（允許神經(jīng)元彼此溝通的事件）是由離子型谷氨酸鹽受體調(diào)控的，這些受體通過打開結(jié)合谷氨酸鹽上的一個(gè)跨膜離子通道發(fā)揮作用,。過去人們對它們的總體結(jié)構(gòu)知之甚少,，但現(xiàn)在Eric Gouaux及其同事報(bào)告了結(jié)合到一個(gè)競爭性拮抗劑上的對AMPA敏感的亞型“大鼠GluA2受體”的X-射線晶體結(jié)構(gòu)。
該受體（如封面圖片所示）具有一個(gè)出乎意料的對稱性和亞單元排列：總體上為雙重對稱,，細(xì)胞外區(qū)域按局部二聚體對的形式來組織,。離子通道區(qū)域表現(xiàn)出四重對稱。這種結(jié)構(gòu)（是根據(jù)來自定點(diǎn)誘變實(shí)驗(yàn)的數(shù)據(jù)獲得的）表明,，對NMDA敏感的受體GluN1 和 GluN2A在總體結(jié)構(gòu)上與GluA2相似,。從這些結(jié)構(gòu)可以推斷出非競爭性拮抗劑和孔阻斷分子對離子通道的激發(fā)、脫敏和抑制機(jī)制,。（生物谷Bioon.com）
2010年廣州-東莞首屆國際小型豬論壇：http://www.minipig.org/
生物谷推薦原始出處：
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.
