scholarly journals Chemical activation of the mechanotransduction channel Piezo1

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ruhma Syeda ◽  
Jie Xu ◽  
Adrienne E Dubin ◽  
Bertrand Coste ◽  
Jayanti Mathur ◽  
...  
Keyword(s):  
Ion Channels ◽  
Lipid Bilayers ◽  
Chemical Activation ◽  
Pressure Sensors ◽  
Inactivation Kinetics ◽  
Mechanical Stimuli ◽  
Functional Studies ◽  
A Cell ◽  
And Function ◽  
Cellular Components

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.

scholarly journals Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective

2020 ◽  
Vol 21 (20) ◽  
pp. 7595
Author(s):  
Anita K. Luu ◽  
Alicia M. Viloria-Petit
Keyword(s):  
Tumour Progression ◽  
Cell Signalling ◽  
Bone Tumour ◽  
Mechanical Stimuli ◽  
Current State ◽  
Organ Systems ◽  
A Cell ◽  
Canine Models ◽  
Improved Design ◽  
And Function

Mechanotransduction is the process in which cells can convert extracellular mechanical stimuli into biochemical changes within a cell. While this a normal process for physiological development and function in many organ systems, tumour cells can exploit this process to promote tumour progression. Here we summarise the current state of knowledge of mechanotransduction in osteosarcoma (OSA), the most common primary bone tumour, referencing both human and canine models and other similar mesenchymal malignancies (e.g., Ewing sarcoma). Specifically, we discuss the mechanical properties of OSA cells, the pathways that these cells utilise to respond to external mechanical cues, and mechanotransduction-targeting strategies tested in OSA so far. We point out gaps in the literature and propose avenues to address them. Understanding how the physical microenvironment influences cell signalling and behaviour will lead to the improved design of strategies to target the mechanical vulnerabilities of OSA cells.

scholarly journals The Form and Function of PIEZO2

2021 ◽  
Vol 90 (1) ◽  
pp. 507-534
Author(s):  
Marcin Szczot ◽  
Alec R. Nickolls ◽  
Ruby M. Lam ◽  
Alexander T. Chesler
Keyword(s):  
Shear Stress ◽  
Ion Channels ◽  
Molecular Level ◽  
Sensory Biology ◽  
Mechanical Stimuli ◽  
Functional Roles ◽  
Form And Function ◽  
The Past ◽  
And Function ◽  
Sense Of Touch

Mechanosensation is the ability to detect dynamic mechanical stimuli (e.g., pressure, stretch, and shear stress) and is essential for a wide variety of processes, including our sense of touch on the skin. How touch is detected and transduced at the molecular level has proved to be one of the great mysteries of sensory biology. A major breakthrough occurred in 2010 with the discovery of a family of mechanically gated ion channels that were coined PIEZOs. The last 10 years of investigation have provided a wealth of information about the functional roles and mechanisms of these molecules. Here we focus on PIEZO2, one of the two PIEZO proteins found in humans and other mammals. We review how work at the molecular, cellular, and systems levels over the past decade has transformed our understanding of touch and led to unexpected insights into other types of mechanosensation beyond the skin.

scholarly journals Asymmetric mechanosensitivity in a eukaryotic ion channel

2017 ◽  
Vol 114 (40) ◽  
pp. E8343-E8351 ◽  
Author(s):  
Michael V. Clausen ◽  
Viwan Jarerattanachat ◽  
Elisabeth P. Carpenter ◽  
Mark S. P. Sansom ◽  
Stephen J. Tucker
Keyword(s):  
Ion Channels ◽  
Molecular Mechanisms ◽  
Asymmetric Structure ◽  
Single Channels ◽  
Mechanical Stimuli ◽  
Diverse Range ◽  
Mechanosensitive Ion Channels ◽  
Functional Studies ◽  
Living Organisms ◽  
Pore Domain

Living organisms perceive and respond to a diverse range of mechanical stimuli. A variety of mechanosensitive ion channels have evolved to facilitate these responses, but the molecular mechanisms underlying their exquisite sensitivity to different forces within the membrane remains unclear. TREK-2 is a mammalian two-pore domain (K2P) K+ channel important for mechanosensation, and recent studies have shown how increased membrane tension favors a more expanded conformation of the channel within the membrane. These channels respond to a complex range of mechanical stimuli, however, and it is uncertain how differences in tension between the inner and outer leaflets of the membrane contribute to this process. To examine this, we have combined computational approaches with functional studies of oppositely oriented single channels within the same lipid bilayer. Our results reveal how the asymmetric structure of TREK-2 allows it to distinguish a broad profile of forces within the membrane, and illustrate the mechanisms that eukaryotic mechanosensitive ion channels may use to detect and fine-tune their responses to different mechanical stimuli.

scholarly journals ION TRAFFIC THROUGH A CELL MEMBRANE — AND HOW ITS 1/f NOISE CONNECTS TO GAMBLER'S RUIN, CATALAN NUMBERS AND ZIPF'S LAW

2011 ◽  
Vol 10 (04) ◽  
pp. 419-430 ◽  
Author(s):  
MARTIN BIER ◽  
JILL GALLAHER
Keyword(s):  
Ion Channels ◽  
Cell Membrane ◽  
Lipid Bilayers ◽  
Catalan Numbers ◽  
Zipf’S Law ◽  
Live Cells ◽  
Voltage Noise ◽  
Zipf's Law ◽  
A Cell ◽  
Gambler’S Ruin

1/f Noise has been observed in currents through ion channels, in currents through pores in lipid bilayers, and in the voltage noise of live cells. In the case of the ion channels and bilayer pores, a mechanism has been proposed and corroborated. The mechanism appears robust and may share an underlying logic with Zipf's Law and Gambler's Ruin.

scholarly journals Mechanotransduction in osteogenesis

2020 ◽  
Vol 9 (1) ◽  
pp. 1-14
Author(s):  
Sarah Stewart ◽  
Alastair Darwood ◽  
Spyros Masouros ◽  
Claire Higgins ◽  
Arul Ramasamy
Keyword(s):  
Bone Formation ◽  
De Novo ◽  
The Body ◽  
Mechanical Stimuli ◽  
Physical Stimulus ◽  
Complex Interplay ◽  
Surrounding Environment ◽  
A Cell ◽  
And Function ◽  
Made In

Bone is one of the most highly adaptive tissues in the body, possessing the capability to alter its morphology and function in response to stimuli in its surrounding environment. The ability of bone to sense and convert external mechanical stimuli into a biochemical response, which ultimately alters the phenotype and function of the cell, is described as mechanotransduction. This review aims to describe the fundamental physiology and biomechanisms that occur to induce osteogenic adaptation of a cell following application of a physical stimulus. Considerable developments have been made in recent years in our understanding of how cells orchestrate this complex interplay of processes, and have become the focus of research in osteogenesis. We will discuss current areas of preclinical and clinical research exploring the harnessing of mechanotransductive properties of cells and applying them therapeutically, both in the context of fracture healing and de novo bone formation in situations such as nonunion. Cite this article: Bone Joint Res 2019;9(1):1–14.

CD38 as an immunomodulator in cancer

2020 ◽  
Vol 16 (34) ◽  
pp. 2853-2861
Author(s):  
Yanli Li ◽  
Rui Yang ◽  
Limo Chen ◽  
Sufang Wu
Keyword(s):  
Multiple Myeloma ◽  
Cell Activation ◽  
Human Tissues ◽  
Transmembrane Glycoprotein ◽  
Cell Activation Marker ◽  
Research Findings ◽  
A Cell ◽  
And Function ◽  
Human Molecule

CD38 is a transmembrane glycoprotein that is widely expressed in a variety of human tissues and cells, especially those in the immune system. CD38 protein was previously considered as a cell activation marker, and today monoclonal antibodies targeting CD38 have witnessed great achievements in multiple myeloma and promoted researchers to conduct research on other tumors. In this review, we provide a wide-ranging review of the biology and function of the human molecule outside the field of myeloma. We focus mainly on current research findings to summarize and update the findings gathered from diverse areas of study. Based on these findings, we attempt to extend the role of CD38 in the context of therapy of solid tumors and expand the role of the molecule from a simple marker to an immunomodulator.

scholarly journals Maturation of the Na,K-ATPase in the Endoplasmic Reticulum in Health and Disease

2021 ◽  
Author(s):  
Vitalii Kryvenko ◽  
Olga Vagin ◽  
Laura A. Dada ◽  
Jacob I. Sznajder ◽  
István Vadász
Keyword(s):  
Endoplasmic Reticulum ◽  
Intracellular Signaling ◽  
Loss Of Function ◽  
Α Subunit ◽  
Rate Limiting Step ◽  
Atpase Subunits ◽  
A Cell ◽  
Health And Disease ◽  
And Function ◽  
Rate Limiting

Abstract The Na,K-ATPase establishes the electrochemical gradient of cells by driving an active exchange of Na+ and K+ ions while consuming ATP. The minimal functional transporter consists of a catalytic α-subunit and a β-subunit with chaperon activity. The Na,K-ATPase also functions as a cell adhesion molecule and participates in various intracellular signaling pathways. The maturation and trafficking of the Na,K-ATPase include co- and post-translational processing of the enzyme in the endoplasmic reticulum (ER) and the Golgi apparatus and subsequent delivery to the plasma membrane (PM). The ER folding of the enzyme is considered as the rate-limiting step in the membrane delivery of the protein. It has been demonstrated that only assembled Na,K-ATPase α:β-complexes may exit the organelle, whereas unassembled, misfolded or unfolded subunits are retained in the ER and are subsequently degraded. Loss of function of the Na,K-ATPase has been associated with lung, heart, kidney and neurological disorders. Recently, it has been shown that ER dysfunction, in particular, alterations in the homeostasis of the organelle, as well as impaired ER-resident chaperone activity may impede folding of Na,K-ATPase subunits, thus decreasing the abundance and function of the enzyme at the PM. Here, we summarize our current understanding on maturation and subsequent processing of the Na,K-ATPase in the ER under physiological and pathophysiological conditions. Graphic Abstract

scholarly journals Combined Effects of Methylated Cytosine and Molecular Crowding on the Thermodynamic Stability of DNA Duplexes

2021 ◽  
Vol 22 (2) ◽  
pp. 947
Author(s):  
Mitsuki Tsuruta ◽  
Yui Sugitani ◽  
Naoki Sugimoto ◽  
Daisuke Miyoshi
Keyword(s):  
Molecular Crowding ◽  
Dna Duplexes ◽  
Crowding Effect ◽  
Backbone Flexibility ◽  
Cpg Dinucleotides ◽  
Key Factor ◽  
Dna Backbone ◽  
A Cell ◽  
Stabilization Effect ◽  
And Function

Methylated cytosine within CpG dinucleotides is a key factor for epigenetic gene regulation. It has been revealed that methylated cytosine decreases DNA backbone flexibility and increases the thermal stability of DNA. Although the molecular environment is an important factor for the structure, thermodynamics, and function of biomolecules, there are few reports on the effects of methylated cytosine under a cell-mimicking molecular environment. Here, we systematically investigated the effects of methylated cytosine on the thermodynamics of DNA duplexes under molecular crowding conditions, which is a critical difference between the molecular environment in cells and test tubes. Thermodynamic parameters quantitatively demonstrated that the methylation effect and molecular crowding effect on DNA duplexes are independent and additive, in which the degree of the stabilization is the sum of the methylation effect and molecular crowding effect. Furthermore, the effects of methylation and molecular crowding correlate with the hydration states of DNA duplexes. The stabilization effect of methylation was due to the favorable enthalpic contribution, suggesting that direct interactions of the methyl group with adjacent bases and adjacent methyl groups play a role in determining the flexibility and thermodynamics of DNA duplexes. These results are useful to predict the properties of DNA duplexes with methylation in cell-mimicking conditions.

scholarly journals Bright Ion Channels and Lipid Bilayers

2013 ◽  
Vol 46 (12) ◽  
pp. 2910-2923 ◽  
Author(s):  
Wiktor SzymaŃski ◽  
Duygu Yilmaz ◽  
ArmaĞan Koçer ◽  
Ben L. Feringa
Keyword(s):  
Ion Channels ◽  
Lipid Bilayers
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