{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T06:11:08Z","timestamp":1793254268643,"version":"4.5.0"},"reference-count":37,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Community in the Marie Sk\u0142odowska-Curie project","doi-asserted-by":"publisher","award":["101120168"],"award-info":[{"award-number":["101120168"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Community in the Marie Sk\u0142odowska-Curie project","doi-asserted-by":"publisher","award":["522062907"],"award-info":[{"award-number":["522062907"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation (DFG) in the Weave project GENIAL","doi-asserted-by":"publisher","award":["101120168"],"award-info":[{"award-number":["101120168"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation (DFG) in the Weave project GENIAL","doi-asserted-by":"publisher","award":["522062907"],"award-info":[{"award-number":["522062907"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Piezo1 is a mechanosensitive non-selective cation channel. Genetic alterations of the channel result in a hematologic phenotype named Hereditary Xerocytosis. With Yoda1 and, more recently, Yoda2, compounds to increase the activity of Piezo1 have become available. However, their concrete effect depends on the nano environment of the channel and hence on the cell type. Here we compare the potency of Yoda1 and Yoda2 in red blood cells (RBCs). We investigate the effect of the compounds on direct channel activity using automated patch clamp, as well as the secondary effects of channel activation on signalling molecules and cellular response. In terms of signalling, we investigate the temporal response of the second messenger Ca2+, and in terms of cellular response, the activity of the G\u00e1rdos channel. The opening of the G\u00e1rdos channel leads to a hyperpolarisation of the RBCs, which is measured by the Macey\u2013Bennekou\u2013Eg\u00e9e (MBE) method. Although the interpretation of the data is not straightforward, we discuss the results in a physiological context and provide recommendations for the use of Yoda1 and Yoda2 to investigate RBCs.<\/jats:p>","DOI":"10.3390\/biom15081110","type":"journal-article","created":{"date-parts":[[2025,8,4]],"date-time":"2025-08-04T09:41:17Z","timestamp":1754300477000},"page":"1110","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Piezo1 Channel Activators Yoda1 and Yoda2 in the Context of Red Blood Cells"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-6824","authenticated-orcid":false,"given":"Min","family":"Qiao","sequence":"first","affiliation":[{"name":"Theoretical Medicine and Biosciences, Medical Faculty, Saarland University, 66421 Homburg, Germany"},{"name":"Dynamics of Fluids, Experimental Physics, Faculty of Natural Science and Technology, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reetta","family":"Penttinen","sequence":"additional","affiliation":[{"name":"Theoretical Medicine and Biosciences, Medical Faculty, Saarland University, 66421 Homburg, Germany"},{"name":"Nanion Technologies, 80339 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-6745-5918","authenticated-orcid":false,"given":"Ariel","family":"Coli","sequence":"additional","affiliation":[{"name":"Dynamics of Fluids, Experimental Physics, Faculty of Natural Science and Technology, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Murciano","sequence":"additional","affiliation":[{"name":"Nanion Technologies, 80339 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6459-1204","authenticated-orcid":false,"given":"Felix M.","family":"Maurer","sequence":"additional","affiliation":[{"name":"Dynamics of Fluids, Experimental Physics, Faculty of Natural Science and Technology, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7788-4594","authenticated-orcid":false,"given":"Christian","family":"Wagner","sequence":"additional","affiliation":[{"name":"Dynamics of Fluids, Experimental Physics, Faculty of Natural Science and Technology, Saarland University, 66123 Saarbr\u00fccken, Germany"},{"name":"Physics and Materials Science Research Unit, University of Luxembourg, 1511 Luxembourg, Luxembourg"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4580-6264","authenticated-orcid":false,"given":"Maria Giustina","family":"Rotordam","sequence":"additional","affiliation":[{"name":"Nanion Technologies, 80339 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6796-9535","authenticated-orcid":false,"given":"Lars","family":"Kaestner","sequence":"additional","affiliation":[{"name":"Theoretical Medicine and Biosciences, Medical Faculty, Saarland University, 66421 Homburg, Germany"},{"name":"Dynamics of Fluids, Experimental Physics, Faculty of Natural Science and Technology, Saarland University, 66123 Saarbr\u00fccken, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1126\/science.1193270","article-title":"Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels","volume":"330","author":"Coste","year":"2010","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/nature10812","article-title":"Piezo Proteins Are Pore-Forming Subunits of Mechanically Activated Channels","volume":"483","author":"Coste","year":"2012","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"10347","DOI":"10.1073\/pnas.1409233111","article-title":"Piezo1, a Mechanically Activated Ion Channel, Is Required for Vascular Development in Mice","volume":"111","author":"Ranade","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nature21407","article-title":"Mechanical Stretch Triggers Rapid Epithelial Cell Division through Piezo1","volume":"543","author":"Gudipaty","year":"2017","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature25744","article-title":"Mechanical Regulation of Stem-Cell Differentiation by the Stretch-Activated Piezo Channel","volume":"555","author":"He","year":"2018","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhou, Z., and Martinac, B. (2023). Mechanisms of PIEZO Channel Inactivation. Int. J. Mol. Sci., 24.","DOI":"10.20944\/preprints202308.1567.v1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e07370","DOI":"10.7554\/eLife.07370","article-title":"Piezo1 Links Mechanical Forces to Red Blood Cell Volume","volume":"4","author":"Cahalan","year":"2015","journal-title":"eLife"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"H24","DOI":"10.1152\/ajpheart.00185.2022","article-title":"Piezo1 Regulates Shear-Dependent Nitric Oxide Production in Human Erythrocytes","volume":"323","author":"Kuck","year":"2022","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1146\/annurev-physiol-022724-105119","article-title":"The Calcium Homeostasis of Human Red Blood Cells in Health and Disease: Interactions of PIEZO1, the Plasma Membrane Calcium Pump, and Gardos Channels","volume":"87","author":"Lew","year":"2025","journal-title":"Annu. Rev. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1182\/blood-2012-04-422253","article-title":"Mutations in the Mechanotransduction Protein PIEZO1 Are Associated with Hereditary Xerocytosis","volume":"120","author":"Zarychanski","year":"2012","journal-title":"Blood"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1038\/ncomms2899","article-title":"Dehydrated Hereditary Stomatocytosis Linked to Gain-of-Function Mutations in Mechanically Activated PIEZO1 Ion Channels","volume":"4","author":"Albuisson","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e179","DOI":"10.3324\/haematol.2018.201160","article-title":"A Novel Gain-of-Function Mutation of Piezo1 Is Functionally Affirmed in Red Blood Cells by High-Throughput Patch Clamp","volume":"104","author":"Rotordam","year":"2019","journal-title":"Haematologica"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1002\/ajh.26192","article-title":"Recent Advances in the Pathophysiology of PIEZO1-related Hereditary Xerocytosis","volume":"96","author":"Jankovsky","year":"2021","journal-title":"Am. J. Hematol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1080\/03630269.2024.2427187","article-title":"Hereditary Hemolytic Anemia Due to PIEZO1 Red Blood Cell Membrane Defect","volume":"48","author":"Dryllis","year":"2024","journal-title":"Hemoglobin"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10366","DOI":"10.1038\/ncomms10366","article-title":"Removal of the Mechanoprotective Influence of the Cytoskeleton Reveals PIEZO1 Is Gated by Bilayer Tension","volume":"7","author":"Cox","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e12088","DOI":"10.7554\/eLife.12088","article-title":"Mechanical Sensitivity of Piezo1 Ion Channels Can Be Tuned by Cellular Membrane Tension","volume":"4","author":"Lewis","year":"2015","journal-title":"eLife"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e201912515","DOI":"10.1085\/jgp.201912515","article-title":"Disruption of Membrane Cholesterol Organization Impairs the Activity of PIEZO1 Channel Clusters","volume":"152","author":"Ridone","year":"2020","journal-title":"J. Gen. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yamaguchi, Y., Allegrini, B., Rapetti-Mauss, R., Picard, V., Gar\u00e7on, L., Kohl, P., Soriani, O., Peyronnet, R., and Guizouarn, H. (2021). Hereditary Xerocytosis: Differential Behavior of PIEZO1 Mutations in the N-Terminal Extracellular Domain Between Red Blood Cells and HEK Cells. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.736585"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1097\/MOH.0000000000000706","article-title":"PIEZO1, Sensing the Touch during Erythropoiesis","volume":"29","author":"Caulier","year":"2022","journal-title":"Curr. Opin. Hematol."},{"key":"ref_20","unstructured":"Garcia, L.R. (2024). Regulation of PIEZO Channels by Membrane Lipids. [Ph.D. Thesis, University of Tennessee Health Science Center]."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e07369","DOI":"10.7554\/eLife.07369","article-title":"Chemical Activation of the Mechanotransduction Channel Piezo1","volume":"4","author":"Syeda","year":"2015","journal-title":"eLife"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"478a","DOI":"10.1016\/j.bpj.2018.11.2585","article-title":"Structural Bases for Chemical and Mechanical Gating in the Piezo1 Channel","volume":"116","author":"Zhang","year":"2019","journal-title":"Biophys. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7467","DOI":"10.1038\/s41467-022-35034-6","article-title":"Membrane Curvature Governs the Distribution of Piezo1 in Live Cells","volume":"13","author":"Yang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Petkova-Kirova, P., Murciano, N., Iacono, G., Jansen, J., Simionato, G., Qiao, M., Van Der Zwaan, C., Rotordam, M.G., John, T., and Hertz, L. (2024). The G\u00e1rdos Channel and Piezo1 Revisited: Comparison between Reticulocytes and Mature Red Blood Cells. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25031416"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"E383","DOI":"10.1002\/ajh.27109","article-title":"Adverse Effects of Delta-9-tetrahydrocannabinol on Sickle Red Blood Cells","volume":"98","author":"Hatem","year":"2023","journal-title":"Am. J. Hematol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/0005-2736(78)90253-5","article-title":"Erythrocyte Membrane Potentials Determined by Hydrogen Ion Distribution","volume":"512","author":"Macey","year":"1978","journal-title":"Biochim. Et. Biophys. Acta BBA Biomembr."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.bioelechem.2008.04.006","article-title":"Evidence for a Random Entry of Ca2+ into Human Red Cells","volume":"73","author":"Bennekou","year":"2008","journal-title":"Bioelectrochemistry"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Alonso, D.M., P\u00e9r\u00e8s, L., Hatem, A., Bouyer, G., and Eg\u00e9e, S. (2021). The Chloride Conductance Inhibitor NS3623 Enhances the Activity of a Non-Selective Cation Channel in Hyperpolarizing Conditions. Front. Physiol., 12.","DOI":"10.3389\/fphys.2021.743094"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1182\/bloodadvances.2020003823","article-title":"Mechanistic Ion Channel Interactions in Red Cells of Patients with G\u00e1rdos Channelopathy","volume":"5","author":"Jansen","year":"2021","journal-title":"Blood. Adv."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Danielczok, J.G., Terriac, E., Hertz, L., Petkova-Kirova, P., Lautenschl\u00e4ger, F., Laschke, M.W., and Kaestner, L. (2017). Red Blood Cell Passage of Small Capillaries Is Associated with Transient Ca2+-Mediated Adaptations. Front. Physiol., 8.","DOI":"10.3389\/fphys.2017.00979"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"20110","DOI":"10.1038\/s41598-020-76979-2","article-title":"Yoda1 and Phosphatidylserine Exposure in Red Cells from Patients with Sickle Cell Anaemia","volume":"10","author":"Wadud","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hatem, A., Poussereau, G., Gachenot, M., P\u00e9r\u00e8s, L., Bouyer, G., and Eg\u00e9e, S. (2023). Dual Action of Dooku1 on PIEZO1 Channel in Human Red Blood Cells. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1222983"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9848","DOI":"10.3390\/ijms14059848","article-title":"Calcium in Red Blood Cells\u2014A Perilous Balance","volume":"14","author":"Bogdanova","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/978-3-030-12457-1_25","article-title":"Calcium Channels and Calcium-Regulated Channels in Human Red Blood Cells","volume":"1131","author":"Kaestner","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"70","DOI":"10.3324\/haematol.2013.086090","article-title":"Piezo1 Plays a Role in Erythrocyte Volume Homeostasis","volume":"99","author":"Faucherre","year":"2014","journal-title":"Haematologica"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5167","DOI":"10.1074\/jbc.M114.604033","article-title":"Protonation of the Human PIEZO1 Ion Channel Stabilizes Inactivation","volume":"290","author":"Bae","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1182\/blood-2017-05-786004","article-title":"Novel Mechanisms of PIEZO1 Dysfunction in Hereditary Xerocytosis","volume":"130","author":"Glogowska","year":"2017","journal-title":"Blood"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/8\/1110\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:21:21Z","timestamp":1760034081000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/8\/1110"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,1]]},"references-count":37,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["biom15081110"],"URL":"https:\/\/doi.org\/10.3390\/biom15081110","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,1]]}}}