Significance The mechanosensitive ion channel Piezo1 plays many important physiological functions. This essential ion channel is selectively activated by a synthetic small molecule called Yoda1. Despite current efforts to develop… Click to show full abstract
Significance The mechanosensitive ion channel Piezo1 plays many important physiological functions. This essential ion channel is selectively activated by a synthetic small molecule called Yoda1. Despite current efforts to develop Yoda1 analogs with potential clinical value, the nature and extent of Piezo1 functions modulated by Yoda1 remain unknown. Here we performed a comprehensive biophysical characterization of the effects of Yoda1 and of its antagonist analog Dooku1. We show that Yoda1 activates Piezo1 by energetically stabilizing and destabilizing conducting and nonconducting Piezo1 conformations, respectively. We further discovered that the electrophysiological effects of Yoda1 strongly depend on membrane potential and temperature, two known physiological Piezo1 modulators. Our study illuminates the complexity by which Piezo1 integrates physical and chemical cues.
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Year Published: 2022
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