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Mirko Moroni, M Rocio Servin-Vences, Raluca Fleischer, Oscar Sánchez-Carranza, Gary R Lewin
Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation...
March 15, 2018: Nature Communications
Martin Loynaz Prieto, Kamyar Firouzi, Butrus T Khuri-Yakub, Merritt Maduke
Ultrasound (US) can modulate the electrical activity of the excitable tissues, but the mechanisms underlying this effect are not understood at the molecular level or in terms of the physical modality through which US exerts its effects. Here, we report an experimental system that allows for stable patch-clamp recording in the presence of US at 43 MHz, a frequency known to stimulate neural activity. We describe the effects of US on two ion channels proposed to be involved in the response of excitable cells to US: the mechanosensitive Piezo1 channel and the voltage-gated sodium channel NaV 1...
March 7, 2018: Ultrasound in Medicine & Biology
Pratibha Narayanan, Meike Hütte, Galina Kudryasheva, Francisco J Taberner, Stefan G Lechner, Florian Rehfeldt, David Gomez-Varela, Manuela Schmidt
Piezo2 ion channels are critical determinants of the sense of light touch in vertebrates. Yet, their regulation is only incompletely understood. We recently identified myotubularin related protein-2 (Mtmr2), a phosphoinositide (PI) phosphatase, in the native Piezo2 interactome of murine dorsal root ganglia (DRG). Here, we demonstrate that Mtmr2 attenuates Piezo2-mediated rapidly adapting mechanically activated (RA-MA) currents. Interestingly, heterologous Piezo1 and other known MA current subtypes in DRG appeared largely unaffected by Mtmr2...
March 9, 2018: ELife
Elizabeth L Evans, Kevin Cuthbertson, Naima Endesh, Baptiste Rode, Nicola M Blythe, Adam J Hyman, Sally J Hall, Hannah J Gaunt, Melanie J Ludlow, Richard Foster, David J Beech
BACKGROUND AND PURPOSE: The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small-molecule agonist but the pharmacology of these channels is otherwise limited. EXPERIMENTAL APPROACH: Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca2+ and Tl+ measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in human umbilical vein endothelial cells (HUVECs) which natively express Piezo1...
March 2, 2018: British Journal of Pharmacology
Boris Martinac, Kate Poole
The ability of cells to sense and respond to their physical environment is fundamental to a broad spectrum of biological processes. Cells express an array of force sensors that can transduce mechanical inputs into biochemical signals, including the mechanically activated ion channels PIEZO1, PIEZO2 and TRPV4. The identification and characterisation of mechanically activated ion channels has proven challenging, as has identifying their mode of activation and regulation in vivo. However, the diverse channelopathies associated with the known channels highlights their physiological importance...
February 20, 2018: International Journal of Biochemistry & Cell Biology
Qiancheng Zhao, Heng Zhou, Shaopeng Chi, Yanfeng Wang, Jianhua Wang, Jie Geng, Kun Wu, Wenhao Liu, Tingxin Zhang, Meng-Qiu Dong, Jiawei Wang, Xueming Li, Bailong Xiao
The mechanosensitive Piezo channels function as key eukaryotic mechanotransducers. However, their structures and mechanogating mechanisms remain unknown. Here we determine the three-bladed, propeller-like electron cryo-microscopy structure of mouse Piezo1 and functionally reveal its mechanotransduction components. Despite the lack of sequence repetition, we identify nine repetitive units consisting of four transmembrane helices each-which we term transmembrane helical units (THUs)-which assemble into a highly curved blade-like structure...
February 22, 2018: Nature
Nathaniel G Dela Paz, John A Frangos
Piezo1 is a mechanosensitive cation channel that is activated by shear stress in endothelial cells (ECs). It has been shown to mediate shear-induced EC responses, including increased calcium influx, and vascular functions, such as vascular tone and blood pressure. Yoda1, a selective Piezo1 activator, has been shown to mimic shear-induced responses in ECs. Since shear-induced calcium influx causes Akt and ERK1/2 activation in ECs, we examined the effects of Yoda1 and the role of Piezo1 on their activation. Here, we show that Yoda1 robustly activates Akt and ERK1/2 in ECs...
February 8, 2018: Biochemical and Biophysical Research Communications
Roberta Russo, Immacolata Andolfo, Francesco Manna, Antonella Gambale, Roberta Marra, Barbara Eleni Rosato, Paola Caforio, Valeria Pinto, Piero Pignataro, Kottayam Radhakrishnan, Sule Unal, Giovanna Tomaiuolo, Gian Luca Forni, Achille Iolascon
Mutations in more than 70 genes cause hereditary anemias (HA), a highly heterogeneous group of rare/low frequency disorders in which we included: hyporegenerative anemias, as congenital dyserythropoietic anemia (CDA) and Diamond-Blackfan anemia; hemolytic anemias due to erythrocyte membrane defects, as hereditary spherocytosis and stomatocytosis; hemolytic anemias due to enzymatic defects. The study describes the diagnostic workflow for HA, based on the development of two consecutive versions of a targeted-NGS panel, including 34 and 71 genes, respectively...
February 3, 2018: American Journal of Hematology
Alexander T Chesler, Marcin Szczot
Near atomic-resolution structures have provided insights into the mechanisms by which the Piezo1 ion channel senses and responds to mechanical stimuli.
January 29, 2018: ELife
Martha Rocio Servin-Vences, Jessica Richardson, Gary R Lewin, Kate Poole
Cartilage tissue lines the joints of mammals, helping to lubricate joint movement and distribute mechanical loads. This tissue is comprised of isolated cells known as chondrocytes which are embedded in an extracellular matrix. Chondrocytes produce and maintain the cartilage by sensing and responding to changing mechanical loads. Mechanosensitive ion channels have been implicated in chondrocyte mechanotransduction and recent studies have shown that both PIEZO1 and TRPV4 can be activated by mechanical stimuli in these cells...
January 23, 2018: Clinical and Experimental Pharmacology & Physiology
M Verónica Donoso, Felipe Hernández, Tania Villalón, Claudio Acuña-Castillo, J Pablo Huidobro-Toro
Endothelial cells participate in extracellular ATP release elicited by mechanosensors. To characterize the dynamic interactions between mechanical and chemical factors that modulate ATP secretion by the endothelium, we assessed and compared the mechanisms participating in the spontaneous (basal) and mechanically stimulated secretion using primary cultures of rat mesentery endothelial cells. ATP/metabolites were determined in the cell media prior to (basal) and after cell media displacement or a picospritzer buffer puff used as mechanical stimuli...
January 19, 2018: Purinergic Signalling
Yijia Pan, Sangpil Yoon, Jie Sun, Ziliang Huang, Changyang Lee, Molly Allen, Yiqian Wu, Ya-Ju Chang, Michel Sadelain, K Kirk Shung, Shu Chien, Yingxiao Wang
While cell-based immunotherapy, especially chimeric antigen receptor (CAR)-expressing T cells, is becoming a paradigm-shifting therapeutic approach for cancer treatment, there is a lack of general methods to remotely and noninvasively regulate genetics in live mammalian cells and animals for cancer immunotherapy within confined local tissue space. To address this limitation, we have identified a mechanically sensitive Piezo1 ion channel (mechanosensor) that is activatable by ultrasound stimulation and integrated it with engineered genetic circuits (genetic transducer) in live HEK293T cells to convert the ultrasound-activated Piezo1 into transcriptional activities...
January 17, 2018: Proceedings of the National Academy of Sciences of the United States of America
Silvia Martin-Almedina, Sahar Mansour, Pia Ostergaard
PIEZO1 is a large mechanosensitive ion channel protein. Diseases associated with PIEZO1 include autosomal recessive generalised lymphatic dysplasia of Fotiou (GLDF) and autosomal dominant dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal oedema (DHS). The two disorders show overlapping features, fetal hydrops/perinatal oedema have been reported in both. Electrophysiological studies suggest opposite mechanisms of action: the mutations identified in GLDF patients cause a loss-of-function mechanism of disease and mutations in DHS patients cause gain of function...
January 13, 2018: Journal of Physiology
Chinky Shiu Chen Liu, Deblina Raychaudhuri, Barnali Paul, Yogaditya Chakrabarty, Amrit Raj Ghosh, Oindrila Rahaman, Arindam Talukdar, Dipyaman Ganguly
TCRs recognize peptides on MHC molecules and induce downstream signaling, leading to activation and clonal expansion. In addition to the strength of the interaction of TCRs with peptides on MHC molecules, mechanical forces contribute to optimal T cell activation, as reflected by the superior efficiency of immobilized TCR-cross-linking Abs compared with soluble Abs in TCR triggering, although a dedicated mechanotransduction module is not identified. We found that the professional mechanosensor protein Piezo1 is critically involved in human T cell activation...
January 12, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Kei Saotome, Swetha E Murthy, Jennifer M Kefauver, Tess Whitwam, Ardem Patapoutian, Andrew B Ward
Piezo1 and Piezo2 are mechanically activated ion channels that mediate touch perception, proprioception and vascular development. Piezos are distinct from other ion channels and their structure remains poorly defined, impeding 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-blade propeller shape with a curved transmembrane region containing at least 26 transmembrane helices per protomer...
December 20, 2017: Nature
Jens G Danielczok, Emmanuel Terriac, Laura Hertz, Polina Petkova-Kirova, Franziska Lautenschläger, Matthias W Laschke, Lars Kaestner
When red blood cells (RBCs) pass constrictions or small capillaries they need to pass apertures falling well below their own cross section size. We used different means of mechanical stimulations (hypoosmotic swelling, local mechanical stimulation, passing through microfluidic constrictions) to observe cellular responses of human RBCs in terms of intracellular Ca2+-signaling by confocal microscopy of Fluo-4 loaded RBCs. We were able to confirm our in vitro results in a mouse dorsal skinfold chamber model showing a transiently increased intracellular Ca2+ when RBCs were passing through small capillaries in vivo...
2017: Frontiers in Physiology
Yusong R Guo, Roderick MacKinnon
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...
December 12, 2017: ELife
Rieko Nakatani, Takashi Murata, Takeshi Usui, Koki Moriyoshi, Toshiki Komeda, Yuichi Masuda, Maiko Kakita-Kobayashi, Tetsuya Tagami, Shinsaku Imashuku, Shigeo Kono, Kazunori Yamada, Akira Shimatsu
Glycated hemoglobin (HbA1c) is a widely used marker of glycemic control but can be affected by hemolytic anemia. Glycated albumin (GA) is also affected in patients with liver cirrhosis. We herein report the assessment of glycemic control in a 41-year-old man with dehydrated hereditary stomatocytosis and a PIEZO1 gene mutation complicated by diabetes mellitus and liver cirrhosis due to hemochromatosis. The estimated HbA1c calculated from the average glucose level obtained by continuous glucose monitoring or by self-monitoring of blood glucose was useful for evaluating the glycemic control in this patient, as HbA1c and GA were unreliable due to the coexisting conditions...
February 15, 2018: Internal Medicine
David J Beech
Piezo1 channels are newly discovered ion channels which have come to the fore as players in endothelial biology. They have a key role as sensors of shear stress, a frictional force which arises in vascular biology because of blood flow. Endothelial Piezo1 channels are critical in murine embryonic development, just after the heart starts to beat and drive blood into the nascent endothelial network. In contrast they are not critical at the adult stage but they are important for performance in whole body physical activity where they have a vascular bed-specific effect to cause mesenteric resistance artery vasoconstriction, achieved through opposition to the vasodilatory mechanism of endothelium-derived hyperpolarization...
December 1, 2017: Journal of Physiology
Immacolata Andolfo, Francesco Manna, Gianluca De Rosa, Barbara Eleni Rosato, Antonella Gambale, Giovanna Tomaiuolo, Antonio Carciati, Roberta Marra, Lucia De Franceschi, Achille Iolascon, Roberta Russo
No abstract text is available yet for this article.
March 2018: Haematologica
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