Direct observation of the conformational states of PIEZO1 DOI Creative Commons
Eric M. Mulhall, Anant Gharpure, Rachel Lee

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7976), P. 1117 - 1125

Published: Aug. 16, 2023

Abstract PIEZOs are mechanosensitive ion channels that convert force into chemoelectric signals 1,2 and have essential roles in diverse physiological settings 3 . In vitro studies proposed PIEZO transduce mechanical through the deformation of extensive blades transmembrane domains emanating from a central ion-conducting pore 4–8 However, little is known about how these interact with their native environment which molecular movements underlie activation. Here we directly observe conformational dynamics individual PIEZO1 molecules cell using nanoscopic fluorescence imaging. Compared previous structural models PIEZO1, show significantly expanded at rest by bending stress exerted plasma membrane. The degree expansion varies dramatically along length blade, where decreased binding strength between subdomains can explain increased flexibility distal blade. Using chemical modulators blade channel activation correlated. Our findings begin to uncover activated environment. More generally, as reliably detect shifts single nanometres populations channels, expect this approach will serve framework for analysis membrane proteins

Language: Английский

Mechanosensitive Ion Channels: Structural Features Relevant to Mechanotransduction Mechanisms DOI Open Access
Peng Jin, Lily Yeh Jan, Yuh Nung Jan

et al.

Annual Review of Neuroscience, Journal Year: 2020, Volume and Issue: 43(1), P. 207 - 229

Published: Feb. 22, 2020

Activation of mechanosensitive ion channels underlies a variety fundamental physiological processes that require sensation mechanical force. Different adapt distinctive structures and mechanotransduction mechanisms to fit their biological roles. How work, especially in animals, has been extensively studied the past decade. Here we review key findings functional structural characterizations these highlight features relevant mechanism each specific channel.

Language: Английский

Citations

210
A mechanism for the activation of the mechanosensitive Piezo1 channel by the small molecule Yoda1 DOI Creative Commons
Wesley M. Botello‐Smith, Wenjuan Jiang, Han Zhang

et al.

Nature Communications, Journal Year: 2019, Volume and Issue: 10(1)

Published: Oct. 3, 2019

Mechanosensitive Piezo1 and Piezo2 channels transduce various forms of mechanical forces into cellular signals that play vital roles in many important biological processes vertebrate organisms. Besides forces, is selectively activated by micromolar concentrations the small molecule Yoda1 through an unknown mechanism. Here, using a combination all-atom molecular dynamics simulations, calcium imaging electrophysiology, we identify allosteric binding pocket located putative mechanosensory domain, approximately 40 Å away from central pore. Our simulations further indicate presence agonist correlates with increased tension-induced motions Yoda1-bound subunit. results suggest model wherein acts as wedge, facilitating force-induced conformational changes, effectively lowering channel's threshold for activation. The identification site will pave way rational design future Piezo modulators clinical value.

Language: Английский

Citations

202
Force Sensing by Piezo Channels in Cardiovascular Health and Disease DOI Creative Commons
David J. Beech, Antreas C. Kalli

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2019, Volume and Issue: 39(11), P. 2228 - 2239

Published: Sept. 19, 2019

Mechanical forces are fundamental in cardiovascular biology, and deciphering the mechanisms by which they act remains a testing frontier research. Here, we raise awareness of 2 recently discovered proteins, Piezo1 Piezo2, assemble as transmembrane triskelions to combine exquisite force sensing with regulated calcium influx. There is emerging evidence for their importance endothelial shear stress secretion, NO generation, vascular tone, angiogenesis, atherosclerosis, permeability remodeling, blood pressure regulation, insulin sensitivity, exercise performance, baroreceptor reflex, there early suggestions relevance cardiac fibroblasts myocytes. Human genetic analysis points significance lymphatic disease, anemia, varicose veins, potentially heart failure, hypertension, aneurysms, stroke. These channels appear be versatile sensors, used creatively inform various force-sensing situations. We discuss emergent concepts controversies suggest that potential new important understanding substantial.

Language: Английский

Citations

199
Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis DOI Creative Commons

Joelle Romac,

Rafiq A. Shahid, Sandip M. Swain

et al.

Nature Communications, Journal Year: 2018, Volume and Issue: 9(1)

Published: April 24, 2018

Merely touching the pancreas can lead to premature zymogen activation and pancreatitis but mechanism is not completely understood. Here we demonstrate that pancreatic acinar cells express mechanoreceptor Piezo1 application of pressure within gland produces pancreatitis. To determine if this effect through activation, induce by intrapancreatic duct instillation agonist Yoda1. Pancreatitis induced prevented a antagonist. In cells, Yoda1 stimulates calcium influx induces calcium-dependent injury. Finally, selective cell-specific genetic deletion protects mice against pressure-induced Thus, in for may explain why develops following on as abdominal trauma, obstruction, pancreatography, or surgery. blockade prevent when manipulation anticipated.

Language: Английский

Citations

196
Myosin-II mediated traction forces evoke localized Piezo1-dependent Ca2+ flickers DOI Creative Commons
Kyle L. Ellefsen, Jesse R. Holt, Alice C. Chang

et al.

Communications Biology, Journal Year: 2019, Volume and Issue: 2(1)

Published: Aug. 7, 2019

Piezo channels transduce mechanical stimuli into electrical and chemical signals to powerfully influence development, tissue homeostasis, regeneration. Studies on Piezo1 have largely focused transduction of "outside-in" forces, its response internal, cell-generated forces remains poorly understood. Here, using measurements endogenous activity traction in native cellular conditions, we show that generate spatially-restricted Piezo1-mediated Ca

Language: Английский

Citations

179
Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels DOI Creative Commons
Dominique Douguet, Éric Honoré

Cell, Journal Year: 2019, Volume and Issue: 179(2), P. 340 - 354

Published: Oct. 1, 2019

Language: Английский

Citations

170
The mechanosensitive Piezo1 channel mediates heart mechano-chemo transduction DOI Creative Commons
Fan Jiang,

Kunlun Yin,

Kun Wu

et al.

Nature Communications, Journal Year: 2021, Volume and Issue: 12(1)

Published: Feb. 8, 2021

Abstract The beating heart possesses the intrinsic ability to adapt cardiac output changes in mechanical load. century-old Frank–Starling law and Anrep effect have documented that stretching during diastolic filling increases its contractile force. However, molecular mechanotransduction mechanism impact on health disease remain elusive. Here we show mechanically activated Piezo1 channel converts stretch of cardiomyocytes into Ca 2+ reactive oxygen species (ROS) signaling, which critically determines activity heart. Either cardiac-specific knockout or overexpression mice results defective ROS signaling development cardiomyopathy, demonstrating a homeostatic role Piezo1. is pathologically upregulated both mouse human diseased hearts via an autonomic response cardiomyocytes. Thus, serves as key mechanotransducer for initiating mechano-chemo transduction consequently maintaining normal function, might represent novel therapeutic target treating diseases.

Language: Английский

Citations

165
Structure, kinetic properties and biological function of mechanosensitive Piezo channels DOI Creative Commons

Xiangzhi Fang,

Ting Zhou,

Jiqian Xu

et al.

Cell & Bioscience, Journal Year: 2021, Volume and Issue: 11(1)

Published: Jan. 9, 2021

Abstract Mechanotransduction couples mechanical stimulation with ion flux, which is critical for normal biological processes involved in neuronal cell development, pain sensation, and red blood volume regulation. Although they are key mechanotransducers, mechanosensitive channels mammals have remained difficult to identify. In 2010, Coste colleagues revealed a novel family of mechanically activated cation eukaryotes, consisting Piezo1 Piezo2 channels. These been proposed as the long-sought-after mammals. exhibit unique propeller-shaped architecture implicated mechanotransduction various processes, including touch balance, cardiovascular Furthermore, several mutations Piezo shown cause multiple hereditary human disorders, such autosomal recessive congenital lymphatic dysplasia. Notably, that dehydrated xerocytosis alter rate channel inactivation, indicating role their kinetics physiology. Given importance understanding process, this review focuses on structural details, kinetic properties potential function mechanosensors. We also briefly diseases caused by genes, these proteins.

Language: Английский

Citations

162
Structure deformation and curvature sensing of PIEZO1 in lipid membranes DOI
Xu-Zhong Yang, Chao Lin, Xudong Chen

et al.

Nature, Journal Year: 2022, Volume and Issue: 604(7905), P. 377 - 383

Published: April 6, 2022

Language: Английский

Citations

157
Tethering Piezo channels to the actin cytoskeleton for mechanogating via the cadherin-β-catenin mechanotransduction complex DOI Creative Commons
Jing Wang, Jinghui Jiang, Xu-Zhong Yang

et al.

Cell Reports, Journal Year: 2022, Volume and Issue: 38(6), P. 110342 - 110342

Published: Feb. 1, 2022

The mechanically activated Piezo channel plays a versatile role in conferring mechanosensitivity to various cell types. However, how it incorporates its intrinsic and cellular components effectively sense long-range mechanical perturbation across remains elusive. Here we show that channels are biochemically functionally tethered the actin cytoskeleton via cadherin-β-catenin mechanotransduction complex, whose significantly impairs Piezo-mediated responses. Mechanistically, adhesive extracellular domain of E-cadherin interacts with cap Piezo1, which controls transmembrane gate, while cytosolic tail might interact domains close proximity intracellular gates, allowing direct focus adhesion-cytoskeleton-transmitted force for gating. Specific disruption intermolecular interactions prevents cytoskeleton-dependent gating Piezo1. Thus, propose force-from-filament model complement previously suggested force-from-lipids mechanogating channels, enabling them serve as tunable mechanotransducers.

Language: Английский

Citations

150