钙稳态调节通道的分子调控机理

钙稳态调节通道CALHM是含有四次跨膜的ATP运输通道，受胞外钙离子和外膜电压双重调控，在味觉信号系统中有非常重要的作用。为了深入了解CALHM通道的结构和功能，我们拟在前期高分辨率CALHM1冷冻电镜结构的基础上，综合运用分子模拟，细胞电生理，细胞生物学和冷冻电镜技术，研究以下三个方面内容：CALHM1的ATP分子运输机制；CALHM1的离子通透机制；以及CALHM异二元复合物的三维结构测定。本项目的研究成果将阐明CALHM1通道的工作机理，为设计和开发小分子药物防治阿尔茨海默症提供重要的分子基础。

Calcium homeostasis modulator CALHM is a ATP releasing channel containing four transmembrane membranes, which is regulated by extracellular calcium ions and outer membrane voltage, and plays a very important role in the taste signal system. In order to deeply understand the structure and function of the CALHM channel, we intend to comprehensively apply molecular simulation, cell electrophysiology, cell biology, and cryo-electron microscopy on the basis of the previous high-resolution CALHM1 cryo-EM structure to study the following three aspects: ATP molecular transport mechanism; CALHM1 ion permeability mechanism; and three-dimensional structure determination of CALHM hetero binary complex. The research results of this project will clarify the working mechanism of the CALHM1 channel and provide an important molecular basis for the design and development of small molecule drugs for the prevention and treatment of Alzheimer's disease.