title: Chemical activation of the mechanotransduction channel Piezo1.
abstract: Piezo ion channels are activated by various types of mechanical stimuli and function as biological pressure sensors in both vertebrates and invertebrates. To date, mechanical stimuli are the only means to activate Piezo ion channels and whether other modes of activation exist is not known. In this study, we screened ~3.25 million compounds using a cell-based fluorescence assay and identified a synthetic small molecule we termed Yoda1 that acts as an agonist for both human and mouse Piezo1. Functional studies in cells revealed that Yoda1 affects the sensitivity and the inactivation kinetics of mechanically induced responses. Characterization of Yoda1 in artificial droplet lipid bilayers showed that Yoda1 activates purified Piezo1 channels in the absence of other cellular components. Our studies demonstrate that Piezo1 is amenable to chemical activation and raise the possibility that endogenous Piezo1 agonists might exist. Yoda1 will serve as a key tool compound to study Piezo1 regulation and function.
authors.affiliation: Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States.
authors.forename: Ruhma
authors.initials: R
authors.lastname: Syeda
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States.
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Dubin
authors.affiliation: Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coste
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Truc
authors.initials: T
authors.lastname: Huynh
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Matzen
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Lao
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Ingo H
authors.initials: IH
authors.lastname: Engels
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: H Michael
authors.initials: HM
authors.lastname: Petrassi
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schumacher
authors.affiliation: University of California, San Diego, La Jolla, United States.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Montal
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Bandell
authors.affiliation: Department of Molecular and Cellular Neuroscience, Howard Hughes Medical Institute, The Scripps Research Institute, La Jolla, United States.
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
mesh_terms: D000818:Animals; D005453:Fluorescence; D057166:High-Throughput Screening Assays; D006801:Humans; D007473:Ion Channels / Q000819:agonists* / Q000378:metabolism*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D051379:Mice; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D007473:Ion Channels; C515204:PIEZO1 protein, human; D054852:Small Molecule Libraries
keywords: agonist; biophysics; ion channel; mechanotransduction; neuroscience; none; structural biology