在电压关闭的Na+通道中对快速失活的机制性重新解释
Yichen Liu1, Carlos A Z Bassetto2, Bernardo I Pinto2
1Department of Neurobiology, University of Chicago, Chicago, IL, USA.
Nature communications
|August 21, 2023
概括
对于Nav通道失活的正规链盖模型受到挑战. 新的发现揭示了S6螺旋底部的两个疏水环,而不是IFM图案,形成了最终的失活门.
科学领域:
- 分子生物学分子生物学
- 生物物理学的生物物理.
- 离子通道功能 离子通道功能
背景情况:
- 悬挂盖模型,假定IFM图案作为Nav通道中的快速停用门,一直是长期存在的范式.
- 最近的结构数据显示IFM图案与孔隙相距,这与该模型相矛盾.
- 需要重新评估Nav通道快速不活化背后的分子机制.
研究的目的:
- 提出一种新的机制模型,用于Nav通道中的快速失活.
- 为了识别在无活化过程中负责最终孔密闭的分子组件.
- 调查关键结构元素的变化的功能后果涉及到失活.
主要方法:
- 导航通道的高分辨率结构分析.
- 在 Nav1.4.4 中测量离子和门电流.
- 局部定向突变发生以改变疏水环结构.
主要成果:
- 国际货币基金组织 (IFM) 的图案不是直接封闭毛孔的门.
- 在S6螺旋体的细胞内底部有两个疏水环,形成功能失活门.
- 这些环是连续运行的,是IFM绑定下游的.
- 改变这些环的体积会导致泄漏的无活化状态和减少的离子选择性.
结论:
- 对于Nav通道快速不激活的正规挂盖模型需要修订.
- 一个新的分子框架将S6疏水环确定为终端无活化门.
- 这一发现为离子通道门和选择性提供了新的见解.
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