Structural basis of ligand activation and inhibition in a mammalian TRPV4 ion channel
Wenxuan Zhen, Zhijun Zhao, Shenghai Chang, Xiaoying Chen, Yangzhuoqun Wan, Fan Yang
Abstract
The transient receptor potential vanilloid 4 (TRPV4) channel is a polymodal receptor that is activated by warm temperature, osmolarity changes, and many ligands 1 . Like other members in the TRPV family, TRPV4 is critically involved in a plethora of physiological processes like temperature sensation, osmoregulation, and mechanotransduction. Importantly, TRPV4 has the largest number of mutations associated with human diseases 2 among the TRPV channels. Therefore, TRPV4 has been heavily targeted in drug developments 3 against diseases like chronic cough (NCT03372603) and heart failure (NCT02497937 and NCT02119260). Despite the high-resolution structures of all other members in the TRPV family in mammals have been resolved 4 , to date the only peer-reviewed and published structure of TRPV4 is from Xenopus tropicalis (xTRPV4), which is in the apo state with an S4-S5 linker distinct from most of TRPV channels 5 , offering limited information regarding the ligand gating mechanism of this channel.