Sobolevsky Alexander I, Beck Christine, Wollmuth Lonnie P
Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Neuron. 2002 Jan 3;33(1):75-85. doi: 10.1016/s0896-6273(01)00560-8.
Many N-methyl-D-aspartate receptor (NMDAR) channel blockers that have therapeutic potential can be trapped in the closed state. Using a combination of the substituted cysteine accessibility method and open channel blockers, we found that the M3 segment forms the core of the extracellular vestibule, including a deep site for trapping blockers. The M3 segment, as well as more superficial parts of the extracellular vestibule, undergo extensive remodeling during channel closure, but do not define the activation gate, which is located deeper in the pore. Rather, the pore walls lining the extracellular vestibule constrict during channel closure. This movement is essential for coupling ligand binding to activation gate opening and accounts for the different mechanisms of open channel block, including trapping.
许多具有治疗潜力的N-甲基-D-天冬氨酸受体（NMDAR）通道阻滞剂可能被困在关闭状态。通过结合使用取代半胱氨酸可及性方法和开放通道阻滞剂，我们发现M3片段构成了细胞外前庭的核心，包括一个捕获阻滞剂的深部位点。M3片段以及细胞外前庭更浅表的部分在通道关闭期间会经历广泛的重塑，但并不界定位于孔道更深处的激活门。相反，细胞外前庭内衬的孔壁在通道关闭时会收缩。这种运动对于将配体结合与激活门打开相偶联至关重要，并解释了开放通道阻滞的不同机制，包括捕获。
