Arch funds with the Interdisciplinary Center for Clinical Investigation (Interdisziplinares Zentrum fur Klinische Forschung, IZKF) of your University of Wurzburg, Germany (NU, EW: N-260). NU was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG: UE 171-5/1)Additional informationFundingFunder Interdisziplinares Zentrum fur Klinische Forschung, Universitatsklinikum Wurzburg Deutsche Forschungsgemeinschaft Grant reference quantity N-260 943-80-6 MedChemExpress Author Erhard Wischmeyer �� Nurcan Uceyler �� Nurcan UceylerUE 171-5/The funders had no part in study style, data collection and interpretation, or the decision to submit the function for publication. Author contributions Lukas Hofmann, Formal evaluation, Investigation, Methodology, Writing–original draft; Dorothea Hose, Anne Grie ammer, Robert Blum, Formal analysis, Investigation, Writing–review and editing; Frank Doring, Investigation, Writing–review and editing; Sulayman Dib-Hajj, Stephen Waxman, Methodology, Writing–review and editing; Claudia Sommer, Conceptualization, Data curation, Investigation, Writing–original draft; Erhard Wischmeyer, Data curation, Formal analysis, Funding �� acquisition, Investigation, Methodology, Writing–original draft; Nurcan Uceyler, Conceptualization, Information curation, Formal evaluation, Supervision, Funding acquisition, Investigation, Methodology, Writing–original draft, Project administration Author ORCIDs Lukas Hofmann http://orcid.org/0000-0002-8397-1819 Sulayman Dib-Hajj http://orcid.org/0000-0002-4137-1655 �� Nurcan Uceyler http://orcid.org/0000-0001-6973-6428 Ethics Animal Prometryn MedChemExpress experimentation: Our study was approved by the Bavarian State authorities (Regierung von Unterfranken, # 54/12).Choice letter and Author response Decision letter https://doi.org/10.7554/eLife.39300.013 Author response https://doi.org/10.7554/eLife.39300.Further filesSupplementary files . Mechanical stimulation of Piezo channels provides rise to a mechanically-activated (MA) existing, which swiftly decays due to quick inactivation (Lewis et al., 2017; Gottlieb et al., 2012). Disease-linkedZheng et al. eLife 2019;8:e44003. DOI: https://doi.org/10.7554/eLife.1 ofResearch articleStructural Biology and Molecular Biophysicsmutations in Piezo1 and Piezo2 specifically impact this inactivation approach, suggesting that the standard timing of MA current decay is vital for animal physiology (Wu et al., 2017a). Also, a prolongation of Piezo2 inactivation in somatosensory neurons of tactile-specialist birds suggests that inactivation is involved inside the modulation of complex behaviors (Schneider et al., 2017; Anderson et al., 2017; Schneider et al., 2014). Inactivation is significantly affected by the known modulators of Piezo1: Yoda1 and Jedi1/2 (Lacroix et al., 2018; Wang et al., 2018; Evans et al., 2018; Syeda et al., 2015). However, in spite of its significance for channel function, physiology and pathophysiology, the mechanism of Piezo inactivation remains unknown. Functional Piezo channels are homo-trimers that adopt a exceptional propeller-like architecture comprising a central C-terminal ion-conducting pore and three peripheral N-terminal blades (Figure 1A) (Guo and MacKinnon, 2017; Saotome et al., 2018; Zhao et al., 2018). Each blade is composed of 36 transmembrane (TM) segments and is thought to contribute to sensing tension within the membrane (Guo and MacKinnon, 2017; Haselwandter and MacKinnon, 2018). The pore region, which contains an outer pore helix (OH), an inner pore helix (IH), an additional.