由细胞内质网释放的钙离子与肌肉收缩、神经传递等多种生命活动息息相关。伴随钙离子的释放，内质网内部的负电荷逐渐累计。直到近年来，TRIC离子通道的发现才解释了内质网消除这些负电荷以保证钙离子高效释放的机理。TRIC包括TRIC-A和TRIC-B两个亚型，都属于电压门控离子通道，能够选择性的传递一价阳离子、尤其是钾离子进入内质网内。TRIC被认为与高血压和成骨不全症等疾病有关，作为药物研发的重要靶点受到广泛的关注。但是目前为止尚未取得TRIC的高分辨率立体结构，其离子通道的运行机制、选择性传递一价阳离子特别是钾离子的机理以及离子通道被激活的详细机制均不明确。本课题通过X射线结晶学和电生理学研究TRIC的运行机制。以TRIC的立体结构为基础，筛选对TRIC具有调控作用的化合物，并解析这些化合物与TRIC的复合体结构，研究这些化合物与TRIC具体的结合方式，为新药物的研发提供基础。

Ca2+ release from sarcoplasmic reticulum and endoplasmic reticulum (SR/ER) is involved in various physiological processes such as muscle contraction and neurotransmission. Since Ca2+ release via SR/ER Ca2+ channels would generate a negative potential on the SR/ER luminal side, the molecular mechanism to balance the transient negative potential had been predicted for the efficient Ca2+ release from SR/ER. The TRIC family proteins are trimeric intracellular cation channels, localized at SR/ER. They are recently identified as counter-cation channels to facilitate Ca2+ release from ER and SR. In higher eukaryotes, including human and mouse, two different subtypes of TRICs, TRIC-A and TRIC-B were identified and functionally characterized. Both of TRIC-A and TRIC-B function as monovalent cation channels with a weak preference for K+, and are regulated by membrane-voltage. TRIC channels are associated with malignant hypertension and osteogenesis imperfecta, and accordingly they are recognized as a potential drug target. Despite their physiological importance, the lack of a high resolution structure of TRIC proteins hinders the understanding of the molecular mechanism of cation conduction of TRIC proteins such as ion selectivity and ion channel gating mechanisms. .In our proposal, we will conduct the structural analyses of TRIC proteins as well as the structure-based electrophysiological analyses to understand the molecular mechanism of cation conduction of TRIC proteins. In addition, by utilizing the technical platform for the structural and functional analyses of TRIC proteins, we will identify chemical compounds targeting TRIC proteins, and will determine their complexes with TRIC proteins to provide the structural basis for the development of new compounds for TRIC channels.