Touch, Tension, and Transduction - The Function and Regulation of Piezo Ion Channels.
TL;DR: The many aspects of Piezos function that remain mysterious are discussed, including how Piezos convert a variety of mechanical stimuli into channel activation and subsequent inactivation, and what molecules and mechanisms modulate Piezo function.
About: This article is published in Trends in Biochemical Sciences.The article was published on 2017-01-01 and is currently open access. It has received 336 citations till now. The article focuses on the topics: Mechanotransduction.
Citations
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TL;DR: A high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer provides a foundation to dissect further how Piezo channels are regulated by mechanical force.
Abstract: Piezo1 and Piezo2 are mechanically activated ion channels that mediate touch perception, proprioception and vascular development. Piezo proteins are distinct from other ion channels and their structure remains poorly defined, which impedes detailed study of their gating and ion permeation properties. Here we report a high-resolution cryo-electron microscopy structure of the mouse Piezo1 trimer. The detergent-solubilized complex adopts a three-bladed propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer. The flexible propeller blades can adopt distinct conformations, and consist of a series of four-transmembrane helical bundles that we term Piezo repeats. Carboxy-terminal domains line the central ion pore, and the channel is closed by constrictions in the cytosol. A kinked helical beam and anchor domain link the Piezo repeats to the pore, and are poised to control gating allosterically. The structure provides a foundation to dissect further how Piezo channels are regulated by mechanical force.
345 citations
TL;DR: Cellular mechanotransduction, the process of translating mechanical forces into biological signals, is crucial for a wide range of physiological processes and a role for ion channels in sensing mechanical forces has been proposed for decades, but their identity in mammals remained largely elusive until the discovery of Piezos.
Abstract: Cellular mechanotransduction, the process of translating mechanical forces into biological signals, is crucial for a wide range of physiological processes. A role for ion channels in sensing mechanical forces has been proposed for decades, but their identity in mammals remained largely elusive until the discovery of Piezos. Recent research on Piezos has underscored their importance in somatosensation (touch perception, proprioception and pulmonary respiration), red blood cell volume regulation, vascular physiology and various human genetic disorders.
316 citations
TL;DR: A hypothesis in which the membrane deformation changes upon channel opening can account for highly sensitive mechanical gating in the setting of a narrow, cation-selective pore is presented.
Abstract: Mechanosensitive ion channels convert external mechanical stimuli into electrochemical signals for critical processes including touch sensation, balance, and cardiovascular regulation. The best understood mechanosensitive channel, MscL, opens a wide pore, which accounts for mechanosensitive gating due to in-plane area expansion. Eukaryotic Piezo channels have a narrow pore and therefore must capture mechanical forces to control gating in another way. We present a cryo-EM structure of mouse Piezo1 in a closed conformation at 3.7A-resolution. The channel is a triskelion with arms consisting of repeated arrays of 4-TM structural units surrounding a pore. Its shape deforms the membrane locally into a dome. We present a hypothesis in which the membrane deformation changes upon channel opening. Quantitatively, membrane tension will alter gating energetics in proportion to the change in projected area under the dome. This mechanism can account for highly sensitive mechanical gating in the setting of a narrow, cation-selective pore.
252 citations
Cites background from "Touch, Tension, and Transduction - ..."
...Piezo ion channels, Piezo1 and Piezo2, are mechanosensitive channels (MS channels) that underlie force-detection in eukaryotic cells (Coste et al., 2010; Wu et al., 2017)....
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TL;DR: An overview of sensory transduction and neural circuits in the ENS is provided, yielding insights into the generation of gastrointestinal motility.
Abstract: The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical for determining how deficits in neurogenic motor patterns arise. Knowledge of how distension or chemical stimulation of the bowel evokes sensory responses in the ENS and central nervous system have progressed, including critical elements that underlie the mechanotransduction of distension-evoked colonic peristalsis. Contrary to original thought, evidence suggests that mucosal serotonin is not required for peristalsis or colonic migrating motor complexes, although it can modulate their characteristics. Chemosensory stimuli applied to the lumen can release substances from enteroendocrine cells, which could subsequently modulate ENS activity. Advances have been made in optogenetic technologies, such that specific neurochemical classes of enteric neurons can be stimulated. A major focus of this Review will be the latest advances in our understanding of how intrinsic sensory neurons in the ENS detect and respond to sensory stimuli and how these mechanisms differ from extrinsic sensory nerve endings in the gut that underlie the gut-brain axis.
246 citations
TL;DR: The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels.
Abstract: The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
244 citations
References
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TL;DR: Two genes that encode proteins, Piezo1 and Piezo2, are identified, which are required for mechanically stimulated cation conductance in these cells and in cultured dorsal root ganglion neurons, and it is proposed that Piezos are components of MA cation channels.
Abstract: Mechanical stimuli drive many physiological processes, including touch and pain sensation, hearing, and blood pressure regulation. Mechanically activated (MA) cation channel activities have been recorded in many cells, but the responsible molecules have not been identified. We characterized a rapidly adapting MA current in a mouse neuroblastoma cell line. Expression profiling and RNA interference knockdown of candidate genes identified Piezo1 (Fam38A) to be required for MA currents in these cells. Piezo1 and related Piezo2 (Fam38B) are vertebrate multipass transmembrane proteins with homologs in invertebrates, plants, and protozoa. Overexpression of mouse Piezo1 or Piezo2 induced two kinetically distinct MA currents. Piezos are expressed in several tissues, and knockdown of Piezo2 in dorsal root ganglia neurons specifically reduced rapidly adapting MA currents. We propose that Piezos are components of MA cation channels.
1,928 citations
"Touch, Tension, and Transduction - ..." refers background or methods in this paper
...(A) Macroscopic methods for stimulating large populations of Piezo channels, whose activity can be measured with electrophysiology or through calcium imaging [1,13,14,18]....
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...While roles of Piezos in some modalities of mechanotransduction are now well-established, other mechanotransduction processes have been shown to be independent of Piezos: Piezo2 ablation does not reduce either intermediately or slowly adapting mechanical responses of DRG neurons (to which the protein Tentonin 3 was recently proposed to contribute) or responses to harsh mechanical touch in mice [1,33,42]; additionally, mechanotransduction in the hair cells of the inner ear is not dependent on Piezo1 [43]....
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...7 ms, respectively, as measured with ‘poke’) (Figure 1) [1,3]....
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...Across species, Piezos are very large proteins (2521 and 2752 amino acids for human Piezo1 and human Piezo2, respectively) with numerous (>14) predicted transmembrane (TM) domains per subunit and, strikingly, no homology to other known proteins [1]....
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...Piezo Proteins: True Mechanically Activated Ion Channels? Piezo proteins are pore-forming subunits of ion channels that open in response to mechanical stimuli, allowing positively charged ions, including calcium, to flow into the cell (Figure 1) [1]....
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TL;DR: Measurements of channel gating in model systems of membrane proteins with their lipid partners are confirming predictions of simple models, and the free-energy cost of such perturbations can be estimated quantitatively.
Abstract: Studies of membrane proteins have revealed a direct link between the lipid environment and the structure and function of some of these proteins Although some of these effects involve specific chemical interactions between lipids and protein residues, many can be understood in terms of protein-induced perturbations to the membrane shape The free-energy cost of such perturbations can be estimated quantitatively, and measurements of channel gating in model systems of membrane proteins with their lipid partners are now confirming predictions of simple models
887 citations
"Touch, Tension, and Transduction - ..." refers background in this paper
...Moreover, based on the strongly curved shape of the blades, Piezo itself could induce locally distinct membrane curvature, thickness, and tension, and thereby create an equilibrium between externally and locally induced membrane properties [56]....
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...Mechanical force can be directly transmitted to the channel through lateral tension in the membrane bilayer, whereby the conformation with the greater cross-sectional area is favored under higher tension [56]....
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TL;DR: It is shown that Drosophila melanogaster Piezo (DmPiezo, also called CG8486) 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, demonstrating that Piezo proteins are an evolutionarily conserved ion channel family involved in mechanotransduction.
Abstract: Mechanotransduction has an important role in physiology. Biological processes including sensing touch and sound waves require as-yet-unidentified cation channels that detect pressure. Mouse Piezo1 (MmPiezo1) and MmPiezo2 (also called Fam38a and Fam38b, respectively) induce mechanically activated cationic currents in cells; however, it is unknown whether Piezo proteins are pore-forming ion channels or modulate ion channels. Here we show that Drosophila melanogaster Piezo (DmPiezo, also called CG8486) 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. MmPiezo1 assembles as a ∼1.2-million-dalton homo-oligomer, with no evidence of other proteins in this complex. Purified MmPiezo1 reconstituted into asymmetric lipid bilayers and liposomes forms ruthenium-red-sensitive ion channels. These data demonstrate that Piezo proteins are an evolutionarily conserved ion channel family involved in mechanotransduction. Large transmembrane proteins of the Piezo family assemble as tetramers to form a new class of ion channel that can be activated by mechanical force. Many tissues are able to detect and respond to mechanical forces, and this mechanical sensitivity has been implicated in many biological processes and diseases, including touch, pain, deafness and hypertension. The conversion of mechanical force into biological signals, or 'mechanotransduction', is thought to involve specialized cation channels. In a pair of papers, Ardem Patapoutian and colleagues establish that the large transmembrane proteins of the 'Piezo' family — conserved from animals to plants and protozoa — are among the long-sought-after mechanically activated ion channels. Coste et al. show that the Drosophila melanogaster Piezo protein induces mechanically activated cationic currents in human embryonic kidney cells, establishing functional conservation. Comparison of the mechanically activated currents induced by mouse and fly Piezos reveals ion-channel activities with unique pore properties, suggesting that Piezos are bona fide ion channels. Kim et al. show that D. melanogaster Piezo is essential for sensing mechanical pain in fruitflies, giving the first demonstration that Piezos are physiologically relevant mechanosensors in vivo.
765 citations
TL;DR: Piezo1 channels are shown as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology and the data suggest that Piezo 1 channels function as pivotal integrators in vascular biology.
Abstract: The mechanisms by which physical forces regulate endothelial cells to determine the complexities of vascular structure and function are enigmatic. Studies of sensory neurons have suggested Piezo proteins as subunits of Ca(2+)-permeable non-selective cationic channels for detection of noxious mechanical impact. Here we show Piezo1 (Fam38a) channels as sensors of frictional force (shear stress) and determinants of vascular structure in both development and adult physiology. Global or endothelial-specific disruption of mouse Piezo1 profoundly disturbed the developing vasculature and was embryonic lethal within days of the heart beating. Haploinsufficiency was not lethal but endothelial abnormality was detected in mature vessels. The importance of Piezo1 channels as sensors of blood flow was shown by Piezo1 dependence of shear-stress-evoked ionic current and calcium influx in endothelial cells and the ability of exogenous Piezo1 to confer sensitivity to shear stress on otherwise resistant cells. Downstream of this calcium influx there was protease activation and spatial reorganization of endothelial cells to the polarity of the applied force. The data suggest that Piezo1 channels function as pivotal integrators in vascular biology.
710 citations
"Touch, Tension, and Transduction - ..." refers background in this paper
...Shear stress, which occurs upon the flow of blood along walls of arterial cells, also activates Piezo1, and can be experimentally applied by placing a cell next to a superfusion pipette or in a microfluidic chamber [14,15]....
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...The involvement of Piezo1 in cell motility may explain the link between upregulated Piezo1-mediated activity in the breast cancer line MCF-7 and reduced survival rates in patients with increased Piezo1 mRNA levels in the primary tumor [15]....
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...A global knockout of Piezo1 in mouse is lethal during midgestation, owing at least in part to disrupted development of the vasculature system [14,15]....
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TL;DR: It is found that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.
Abstract: The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive. Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell-neurite complexes. It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron; however, major aspects of touch sensation remain intact without Merkel cell activity. Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.
613 citations
"Touch, Tension, and Transduction - ..." refers background in this paper
...While roles of Piezos in some modalities of mechanotransduction are now well-established, other mechanotransduction processes have been shown to be independent of Piezos: Piezo2 ablation does not reduce either intermediately or slowly adapting mechanical responses of DRG neurons (to which the protein Tentonin 3 was recently proposed to contribute) or responses to harsh mechanical touch in mice [1,33,42]; additionally, mechanotransduction in the hair cells of the inner ear is not dependent on Piezo1 [43]....
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...Likewise, an inducible knockout of Piezo2 from DRG neurons (Advil-creERT2;Piezo2) nearly abolishes rapidly adapting, mechanically activated currents in these cells, causing severe deficits in multiple assays designed to test response to innocuous touch and gait stability [33]....
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...Like for Piezo1, global knockout of Piezo2 in mouse is also lethal, with pups dying at birth [33]....
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