Piezo1 links mechanical forces to red blood cell volume
- Howard Hughes Medical Institute, The Scripps Research Institute, United States
- University of California, San Diego, United States
- Genomics Institute of the Novartis Research Foundation, United States
Abstract
Red blood cells (RBCs) experience significant mechanical forces while recirculating, but the consequences of these forces are not fully understood. Recent work has shown that gain-of-function mutations in mechanically-activated Piezo1 cation channels are associated with the dehydrating RBC disease Xerocytosis, implicating a role of mechanotransduction in RBC volume regulation. However, the mechanisms by which these mutations result in RBC dehydration are unknown. Here we show that RBCs exhibit robust calcium entry in response to mechanical stretch, and that this entry is dependent on Piezo1 expression. Furthermore, RBCs from blood-cell-specific Piezo1 conditional knockout mice are overhydrated and exhibit increased fragility both in vitro and in vivo. Finally, we show that Yoda1, a chemical activator of Piezo1, causes calcium influx and subsequent dehydration of RBCs via downstream activation of the KCa3.1 Gardos channel, directly implicating Piezo1 signaling in RBC volume control. Therefore, mechanically-activated Piezo1 plays an essential role in RBC volume homeostasis.
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Ethics
Animal experimentation: All animal procedures were approved by the TSRI Institutional Animal Care and Use Committee (#08-0136).
Copyright
© 2015, Cahalan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Piezo1 links mechanical forces to red blood cell volume
eLife 4:e07370.
https://doi.org/10.7554/eLife.07370
Further reading
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- Structural Biology and Molecular Biophysics
- Neuroscience
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.
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