Nat. Commun.: Xiao Bailong research group, School of pharmacy, Tsinghua University reports on the small molecule agonists of mechanically gated piezo 1 ion channel and its activation mechanism

Recently, naturecommunications published on-line the title of "alever like transmission pathway for long distance chemical - and mechano gating of the mechanosensitive piezo1 channel" by Xiao Bailong research group, DOI: 10.1038/s41467-018-03570-9 ）In this paper, we report a new class of small molecular compound agonists of piezo1 channel and their molecular mechanism of activation of piezo1 channel This study not only promotes the understanding of the pharmacology and molecular mechanism of piezo channel, but also provides research methods and ideas for the further development of small molecular drugs based on piezo channel Mechanical gated piezo channel is the first type of mechanical gated non selective cation channel found in mammalian cells As a mechanical force receptor located on the cell membrane, it can be activated by different forms of mechanical forces such as squeezing, stretching and fluid shear force, which can cause cation to enter and leave the cell, and then induce cell excitation and signal transmission The mammalian piezo channel family consists of two members, piezo 1 and piezo 2 Piezo1 is expressed in a variety of cell tissues in vivo, which has been proved to be involved in vascular development and remodeling, blood pressure regulation, red blood cell volume regulation and epithelial cell homeostasis and other important physiological functions Piezo2 expressed in primary sensory nerve cells has been proved to assume the function of molecular receptors in tactile and proprioception The mutation of human piezo1 gene results in hereditary hyperglycemia, hypoplasia of lymphatics and so on, while the mutation of piezo2 gene results in distal joint bending syndrome and tactile perception defect and so on Therefore, piezo channel has very important physiological and pathological functions and is also an important drug target In this latest paper, aiming at the lack of pharmacological tool molecules in piezo channel, its research team first identified two small molecular compound agonists of piezo 1 channel by high-throughput drug screening method, named Jedi Using Jedi as a tool molecule and combining with electrophysiological patch clamp technology, the construction and functional detection of piezo channel mutants, as well as the detection of protein and drug binding by surface plasmon resonance technology, they found that Jedi was bound to the extracellular component of the peripheral blade of piezo 1 channel It is very interesting that when Jedi combines with piezo1, the key mechanical sensing elements of piezo1, including l15-16 and l19-20 in the extracellular loop region and l1342 and l1345 amino acid sites in the long rod structure (beam) in the cell, will be used to activate the central pore area responsible for ion penetration Based on their research results, they put forward the hypothesis that piezo channel uses lever principle to carry out remote compound and mechanical gating They think that piezo 1 channel uses blade composed of nine thus as mechanical force sensor, The beam structure uses the position of l1342 / l1345 as the fulcrum to form an intramolecular lever transfer device, which effectively transfers the subtle mechanical force or small molecular compound sensed by the peripheral Thu and amplifies it to the force used to control the opening of the central pore area, so as to effectively control the opening of its channel and selective cation penetration The discovery of this intramolecular signaling pathway and mechanism provides an important clue for the subsequent development of small drugs in piezo1 channel Wang Yanfeng, Ph.D student of CLS program of 2013 Life College of xiaobailong research group, and Chi Shaopeng, Ph.D student of 2016 medicine college are the first authors of this paper, and researcher xiaobailong is the corresponding author of this paper The He Wei, Zu Lian, Rao Yu and Tang Yefeng research groups of the school of pharmacy provided the compound library for screening, and Dr Guo Huifang and Dr Li Guang of Zu Lian research group carried out the synthesis of piezo1 agonist Dr Wang Li and Dr Zhao Qiancheng of Xiao Bailong research group also participated in part of the research work The research was supported by the National Natural Science Foundation of China and the Ministry of science and Technology (31630090, 2016yfa0500402, 2015cb910102, 314222027, 31371118), supported by the national youth program and Tsinghua University Life Science Joint Center, and supported by the high flux fluorescent calcium imaging platform of Peking University molecular medicine center, drug screening platform of Tsinghua University and protein chemistry platform of biomedical testing center Corresponding author: researcher Xiao Bailong