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      Force-induced conformational changes in PIEZO1

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          Abstract

          Piezo1 is a mechanosensitive channel that converts applied force into electrical signals. Partial molecular structures show a bowl-shaped trimer with extended arms. Here we use cryo-electron microscopy (cryo-EM) to show that Piezo1 adopts different degrees of curvature in lipid vesicles of different size. We also use high-speed atomic force microscopy (HS-AFM) imaging to analyze the deformability of Piezo1 under force in membranes on a mica surface: Piezo1 can be flattened reversibly into the membrane plane. By approximating the absolute force applied, we estimate a range of values for a mechanical spring constant for Piezo1. Both methods demonstrate that Piezo1 can deform its shape towards a planar structure. This deformation could explain how lateral membrane tension can be converted into a conformation-dependent free energy change to gate the Piezo1 channel in response to mechanical perturbations.

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          Most cited references30

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          Piezos are pore-forming subunits of mechanically activated channels

          Mechanotransduction plays a crucial role in physiology. Biological processes including sensing touch and sound waves require yet unidentified cation channels that detect pressure. Mouse piezo1 (mpiezo1) and mpiezo2 induce mechanically activated cationic currents in cells; however, it is unknown if piezos are pore-forming ion channels or modulate ion channels. We show that Drosophila piezo (dpiezo) also induces mechanically activated currents in cells, but through channels with remarkably distinct pore properties including sensitivity to the pore blocker ruthenium red and single channel conductances. mpiezo1 assembles as a ~1.2 million-Dalton tetramer, with no evidence of other proteins in this complex. Finally, purified mpiezo1 reconstituted into asymmetric lipid bilayers and liposomes forms ruthenium red-sensitive ion channels. These data demonstrate that piezos are an evolutionarily conserved ion channel family involved in mechanotransduction.
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            Piezo1, a mechanically activated ion channel, is required for vascular development in mice.

            Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has remained elusive. We previously identified Piezo1 and Piezo2 as mechanically activated cation channels that are expressed in many mechanosensitive cell types. Here, we show that Piezo1 is expressed in endothelial cells of developing blood vessels in mice. Piezo1-deficient embryos die at midgestation with defects in vascular remodeling, a process critically influenced by blood flow. We demonstrate that Piezo1 is activated by shear stress, the major type of mechanical force experienced by endothelial cells in response to blood flow. Furthermore, loss of Piezo1 in endothelial cells leads to deficits in stress fiber and cellular orientation in response to shear stress, linking Piezo1 mechanotransduction to regulation of cell morphology. These findings highlight an essential role of mammalian Piezo1 in vascular development during embryonic development.
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              Is Open Access

              Piezo1 links mechanical forces to red blood cell volume

              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. In this study, 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. DOI: http://dx.doi.org/10.7554/eLife.07370.001
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                Author and article information

                Journal
                Nature
                Nature
                Springer Science and Business Media LLC
                0028-0836
                1476-4687
                August 21 2019
                Article
                10.1038/s41586-019-1499-2
                7258172
                31435018
                1512e241-9778-4746-aed6-cda755311804
                © 2019

                http://www.springer.com/tdm

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