PIEZO1 is a mechanically activated cation channel that undergoes force-induced activation and inactivation. However, its distinct structural states remain undefined. Here, we employed an open-prone PIEZO1-S2472E mutant to capture an intermediate open structure.
View Article and Find Full Text PDFPiezo1 is a mechanically activated cation channel that converts mechanical force into diverse physiological processes. Owing to its large protein size of more than 2,500 amino acids and complex 38-transmembrane helix topology, how Piezo1 is post-translationally modified for regulating its in vivo mechanotransduction functions remains largely unexplored. Here, we show that PKA activation potentiates the mechanosensitivity and slows the inactivation kinetics of mouse Piezo1 and identify the major phosphorylation site, serine-1612 (S1612), that also responds to PKC activation and shear stress.
View Article and Find Full Text PDFNat Rev Mol Cell Biol
November 2024
Mechanical force is an essential physical element that contributes to the formation and function of life. The discovery of the evolutionarily conserved PIEZO family, including PIEZO1 and PIEZO2 in mammals, as bona fide mechanically activated cation channels has transformed our understanding of how mechanical forces are sensed and transduced into biological activities. In this Review, I discuss recent structure-function studies that have illustrated how PIEZO1 and PIEZO2 adopt their unique structural design and curvature-based gating dynamics, enabling their function as dedicated mechanotransduction channels with high mechanosensitivity and selective cation conductivity.
View Article and Find Full Text PDFAlterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8 T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8 T cells.
View Article and Find Full Text PDFAlthough anion channel activities have been demonstrated in sarcoplasmic reticulum/endoplasmic reticulum (SR/ER), their molecular identities and functions remain unclear. Here, we link rare variants of Chloride Channel CLIC Like 1 (CLCC1) to amyotrophic lateral sclerosis (ALS)-like pathologies. We demonstrate that CLCC1 is a pore-forming component of an ER anion channel and that ALS-associated mutations impair channel conductance.
View Article and Find Full Text PDFOptic nerve head (ONH) astrocytes provide structural and metabolic support to neuronal axons in developmental, physiological, and pathological progression. Mechanosensitive properties of astrocytes allow them to sense and respond to mechanical cues from the local environment. We confirmed that ONH astrocytes express the mechanosensitive ion channel Piezo1 in vivo.
View Article and Find Full Text PDFAdult brain activities are generally believed to be dominated by chemical and electrical transduction mechanisms. However, the importance of mechanotransduction mediated by mechano-gated ion channels in brain functions is less appreciated. Here, we show that the mechano-gated Piezo1 channel is expressed in the exploratory processes of astrocytes and utilizes its mechanosensitivity to mediate mechanically evoked Ca responses and ATP release, establishing Piezo1-mediated mechano-chemo transduction in astrocytes.
View Article and Find Full Text PDFPIEZO channels respond to piconewton-scale forces to mediate critical physiological and pathophysiological processes. Detergent-solubilized PIEZO channels form bowl-shaped trimers comprising a central ion-conducting pore with an extracellular cap and three curved and non-planar blades with intracellular beams, which may undergo force-induced deformation within lipid membranes. However, the structures and mechanisms underlying the gating dynamics of PIEZO channels in lipid membranes remain unresolved.
View Article and Find Full Text PDFThe mechanically activated Piezo channel plays a versatile role in conferring mechanosensitivity to various cell types. However, how it incorporates its intrinsic mechanosensitivity and cellular components to effectively sense long-range mechanical perturbation across a cell remains elusive. Here we show that Piezo channels are biochemically and functionally tethered to the actin cytoskeleton via the cadherin-β-catenin mechanotransduction complex, whose perturbation significantly impairs Piezo-mediated responses.
View Article and Find Full Text PDFTMEM120A, a member of the transmembrane protein 120 (TMEM120) family, has a pivotal function in adipocyte differentiation and metabolism, and may also contribute to sensing mechanical pain by functioning as an ion channel named TACAN. Here we report that expression of TMEM120A is not sufficient in mediating poking- or stretch-induced currents in cells and have solved cryo-electron microscopy (cryo-EM) structures of human TMEM120A (TMEM120A) in complex with an endogenous metabolic cofactor (coenzyme A, CoASH) and in the apo form. TMEM120A forms a symmetrical homodimer with each monomer containing an amino-terminal coiled-coil motif followed by a transmembrane domain with six membrane-spanning helices.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
July 2021
Ultrasonic hearing and vocalization are the physiological mechanisms controlling echolocation used in hunting and navigation by microbats and bottleneck dolphins and for social communication by mice and rats. The molecular and cellular basis for ultrasonic hearing is as yet unknown. Here, we show that knockout of the mechanosensitive ion channel PIEZO2 in cochlea disrupts ultrasonic- but not low-frequency hearing in mice, as shown by audiometry and acoustically associative freezing behavior.
View Article and Find Full Text PDFThe evolutionarily conserved Piezo channel family, including Piezo1 and Piezo2 in mammals, serves as versatile mechanotransducers in various cell types and consequently governs fundamental pathophysiological processes ranging from vascular development to the sense of gentle touch and tactile pain. Piezo1/2 possess a unique 38-transmembrane (TM) helix topology and form a homotrimeric propeller-shaped structure comprising a central ion-conducting pore and three peripheral mechanosensing blades. The unusually curved TM region of the three blades shapes a signature nano-bowl configuration with potential to generate large in-plane membrane area expansion, which might confer exquisite mechanosensitivity to Piezo channels.
View Article and Find Full Text PDFThe beating heart possesses the intrinsic ability to adapt cardiac output to changes in mechanical load. The century-old Frank-Starling law and Anrep effect have documented that stretching the heart during diastolic filling increases its contractile force. However, the molecular mechanotransduction mechanism and its impact on cardiac health and disease remain elusive.
View Article and Find Full Text PDFWhile the concept of intercellular mechanical communication has been revealed, the mechanistic insights have been poorly evidenced in the context of myofibroblast-fibroblast interaction during fibrosis expansion. Here we report and systematically investigate the mechanical force-mediated myofibroblast-fibroblast cross talk via the fibrous matrix, which we termed paratensile signaling. Paratensile signaling enables instantaneous and long-range mechanotransduction via collagen fibers (less than 1 s over 70 μm) to activate a single fibroblast, which is intracellularly mediated by DDR2 and integrin signaling pathways in a calcium-dependent manner through the mechanosensitive Piezo1 ion channel.
View Article and Find Full Text PDFThe mechanosensitive Piezo1 and Piezo2 channels convert mechanical force into cation permeation. However, their precise mechanogating and regulatory mechanisms remain elusive. Here, we report that Piezo1 utilizes three lateral ion-conducting portals equipped with physical gates for cooperative gating and splicing regulation.
View Article and Find Full Text PDFAnnu Rev Pharmacol Toxicol
January 2020
The mechanically activated Piezo channels, including Piezo1 and Piezo2 in mammals, function as key mechanotransducers for converting mechanical force into electrochemical signals. This review highlights key evidence for the potential of Piezo channel drug discovery. First, both mouse and human genetic studies have unequivocally demonstrated the prominent role of Piezo channels in various mammalian physiologies and pathophysiologies, validating their potential as novel therapeutic targets.
View Article and Find Full Text PDFPIEZO2 is a mechanosensitive cation channel that has a key role in sensing touch, tactile pain, breathing and blood pressure. Here we describe the cryo-electron microscopy structure of mouse PIEZO2, which is a three-bladed, propeller-like trimer that comprises 114 transmembrane helices (38 per protomer). Transmembrane helices 1-36 (TM1-36) are folded into nine tandem units of four transmembrane helices each to form the unusual non-planar blades.
View Article and Find Full Text PDFMechanical load of the skeleton system is essential for the development, growth, and maintenance of bone. However, the molecular mechanism by which mechanical stimuli are converted into osteogenesis and bone formation remains unclear. Here we report that Piezo1, a bona fide mechanotransducer that is critical for various biological processes, plays a critical role in bone formation.
View Article and Find Full Text PDFTouch and mechanical pain represent distinct, but interactive, modalities of mechanosensation. However, the molecular mechanisms underlying these mechanotransduction processes remain incompletely understood. Here, we show that deletion of the mechanically activated and rapidly adapting Piezo2 channel in a portion of the low-threshold mechanoreceptors and a majority of the IB4-positive nociceptors impairs touch but sensitizes mechanical pain in mice.
View Article and Find Full Text PDFMammals possess a remarkable ability to sense subtle temperature deviations from the thermoneutral skin temperature of ~33 °C, which ensures precise warm sensation. However, the underlying mechanisms remain unclear. Here we show that STIM1, an endoplasmic reticulum (ER) resident transmembrane protein that responds to both ER Ca depletion and heat, mediates temperature-induced Ca influx in skin keratinocytes via coupling to Orai Ca channels in plasma membrane.
View Article and Find Full Text PDFThe evolutionarily conserved Piezo proteins, including Piezo1 and Piezo2, constitute a bona fide class of mechanosensitive (MS) cation channels, which play critical roles in various mammalian physiologies, including sensation of touch, proprioception and regulation of vascular development, and blood pressure. Furthermore, mutations in Piezos have been linked to various human genetic diseases, validating their potential as therapeutic targets. Thus, it is pivotal to understand how Piezo channels effectively convert mechanical force into selective cation permeation, and therefore precisely control the various mechanotransduction processes.
View Article and Find Full Text PDFIn Extended Data Fig. 9a of this Article, the bottom micrographs of mPiezo1-ΔL3-4-IRES-GFP and mPiezo1-ΔL7-8-IRES-GFP (labelled 'permeabilized') are inadvertently the same images. The corrected figure panels are shown in the accompanying Amendment.
View Article and Find Full Text PDFVoltage-gated sodium (Na) channels, which are responsible for action potential generation, are implicated in many human diseases. Despite decades of rigorous characterization, the lack of a structure of any human Na channel has hampered mechanistic understanding. Here, we report the cryo-electron microscopy structure of the human Na1.
View Article and Find Full Text PDFThe NLRP3 inflammasome senses a range of cellular disturbances, although no consensus exists regarding a common mechanism. Canonical NLRP3 activation is blocked by high extracellular K, regardless of the activating signal. We report here that canonical NLRP3 activation leads to Ca flux and increased calpain activity.
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