{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:17:20Z","timestamp":1785406640544,"version":"3.56.0"},"posted":{"date-parts":[[2025,4,6]]},"group-title":"Biophysics","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,6]],"date-time":"2025-04-06T00:00:00Z","timestamp":1743897600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["DC016868"],"award-info":[{"award-number":["DC016868"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DC019701"],"award-info":[{"award-number":["DC019701"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DC014254"],"award-info":[{"award-number":["DC014254"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]},{"award":["DC000096"],"award-info":[{"award-number":["DC000096"]}],"id":[{"id":"https:\/\/ror.org\/04mhx6838","id-type":"ROR","asserted-by":"publisher"}]},{"award":["RS-2024-00406555"],"award-info":[{"award-number":["RS-2024-00406555"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2022R1A2C3003700"],"award-info":[{"award-number":["2022R1A2C3003700"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["3250793"],"award-info":[{"award-number":["3250793"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"crossref","award":["240021"],"award-info":[{"award-number":["240021"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Sensory hair cells detect sound and balance through their apically located stereocilia bundles, converting mechanical stimuli into electrical signals via mechano-electrical transduction (MET) channels. These channels at the lower end of extracellular tip links connecting adjacent stereocilia are gated by tension. A key regulatory process of MET is\n                  <jats:italic>slow adaptation<\/jats:italic>\n                  , thought to enhance the auditory system\u2019s dynamic range. Traditionally, this process has been attributed to myosin motor activity. Here, we challenge this prevailing model and provide evidence for an alternative mechanism in which\n                  <jats:italic>phosphatidylinositol 4,5-bisphosphate<\/jats:italic>\n                  (PIP\n                  <jats:sub>2<\/jats:sub>\n                  ) modulates slow adaptation via interactions with the MET complex protein TMIE. Remarkably, adaptation was rescued by exogenous PIP\n                  <jats:sub>2<\/jats:sub>\n                  even when myosin motors were inhibited, highlighting PIP\n                  <jats:sub>2<\/jats:sub>\n                  \u2019s central role. Disruption of TMIE, a PIP\n                  <jats:sub>2<\/jats:sub>\n                  -binding protein, also impaired adaptation, and we implicate a PIP\n                  <jats:sub>2<\/jats:sub>\n                  binding site between the channel candidate TMC1 and TMIE to mediate slow adaptation. These findings support a revised model in which PIP\n                  <jats:sub>2<\/jats:sub>\n                  \u2013TMIE\/TMC1 interactions mediate slow adaptation in hair cells.\n                <\/jats:p>","DOI":"10.1101\/2025.04.01.646713","type":"posted-content","created":{"date-parts":[[2025,4,7]],"date-time":"2025-04-07T03:51:19Z","timestamp":1743997879000},"source":"Crossref","is-referenced-by-count":2,"title":["PIP\n                  <sub>2<\/sub>\n                  -TMIE Interactions Drive Mammalian Hair Cell Slow Adaptation Independently of Myosin Motors"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9609-0789","authenticated-orcid":false,"given":"Giusy A.","family":"Caprara","sequence":"first","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujin","family":"Jun","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO"},{"name":"Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea"},{"name":"School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye-Ri","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO"},{"name":"Advanced Bio-Resource Research Center, Kyungpook National University, Daegu, Republic of Korea"},{"name":"Department of Immunology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel J.","family":"Olgu\u00edn-Orellana","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n, 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yein Christina","family":"Park","sequence":"additional","affiliation":[{"name":"Section on Sensory Physiology and Biophysics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD"},{"name":"Graduate Program in Cell, Molecular, Developmental Biology and Biophysics, Johns Hopkins University, Baltimore, MD, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Mart\u00ednez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n, 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5396-6181","authenticated-orcid":false,"given":"Sihan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Virginia, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5796-6875","authenticated-orcid":false,"given":"Angela","family":"Ballesteros","sequence":"additional","affiliation":[{"name":"Section on Sensory Physiology and Biophysics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda, Facultad de Ciencias Biol\u00f3gicas, Universidad de Concepci\u00f3n, Concepci\u00f3n, 4030000, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Unkyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea"},{"name":"Advanced Bio-Resource Research Center, Kyungpook National University, Daegu, Republic of Korea"},{"name":"School of Life Sciences, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3047-0874","authenticated-orcid":false,"given":"Jung-Bum","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, University of Virginia, Charlottesville, VA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2208-6779","authenticated-orcid":false,"given":"Anthony W.","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071404451070000_2025.04.01.646713v2.1","doi-asserted-by":"crossref","unstructured":"Peng, A. W. , Salles, F. T. , Pan, B. & Ricci, A. J . Integrating the biophysical and molecular mechanisms of auditory hair cell mechanotransduction. Nat Commun 2, 523.","DOI":"10.1038\/ncomms1533"},{"key":"2026071404451070000_2025.04.01.646713v2.2","doi-asserted-by":"crossref","unstructured":"Wu, Y.-C. , Ricci, A. J. & Fettiplace, R . Two Components of Transducer Adaptation in Auditory Hair Cells. J Neurophysiol 82, 2171\u20132181.","DOI":"10.1152\/jn.1999.82.5.2171"},{"key":"2026071404451070000_2025.04.01.646713v2.3","doi-asserted-by":"crossref","unstructured":"Caprara, G. A. & Peng, A. W . Mechanotransduction in mammalian sensory hair cells. Mol Cell Neurosci 120, 103706.","DOI":"10.1016\/j.mcn.2022.103706"},{"key":"2026071404451070000_2025.04.01.646713v2.4","doi-asserted-by":"crossref","unstructured":"Holt, J. R. et al. A chemical-genetic strategy implicates myosin-1c in adaptation by hair cells. Cell 108, 371\u2013381.","DOI":"10.1016\/S0092-8674(02)00629-3"},{"key":"2026071404451070000_2025.04.01.646713v2.5","doi-asserted-by":"crossref","unstructured":"Stauffer, E. A. et al. Fast adaptation in vestibular hair cells requires Myosin-1c activity. Neuron 47, 541\u2013553.","DOI":"10.1016\/j.neuron.2005.07.024"},{"key":"2026071404451070000_2025.04.01.646713v2.6","doi-asserted-by":"crossref","unstructured":"Eatock, R. A. , Corey, D. P. & Hudspeth, A. J . Adaptation of mechanoelectrical transduction in hair cells of the bullfrog\u2019s sacculus. J Neurosci 7, 2821\u20132836.","DOI":"10.1523\/JNEUROSCI.07-09-02821.1987"},{"key":"2026071404451070000_2025.04.01.646713v2.7","doi-asserted-by":"crossref","unstructured":"Howard, J. & Hudspeth, A. J . Mechanical relaxation of the hair bundle mediates adaptation in mechanoelectrical transduction by the bullfrog\u2019s saccular hair cell. Proc Natl Acad Sci U S A 84, 3064\u20133068.","DOI":"10.1073\/pnas.84.9.3064"},{"key":"2026071404451070000_2025.04.01.646713v2.8","doi-asserted-by":"crossref","unstructured":"Yamoah, E. N. & Gillespie, P. G . Phosphate analogs block adaptation in hair cells by inhibiting adaptation-motor force production. Neuron 17, 523\u2013533.","DOI":"10.1016\/S0896-6273(00)80184-1"},{"key":"2026071404451070000_2025.04.01.646713v2.9","doi-asserted-by":"crossref","unstructured":"Assad, J. A. & Corey, D. P . An active motor model for adaptation by vertebrate hair cells. J Neurosci 12, 3291\u20133309.","DOI":"10.1523\/JNEUROSCI.12-09-03291.1992"},{"key":"2026071404451070000_2025.04.01.646713v2.10","doi-asserted-by":"crossref","unstructured":"Caprara, G. A. , Mecca, A. A. & Peng, A. W . Decades-old model of slow adaptation in sensory hair cells is not supported in mammals. Sci Adv 6, eabb4922.","DOI":"10.1126\/sciadv.abb4922"},{"key":"2026071404451070000_2025.04.01.646713v2.11","doi-asserted-by":"crossref","unstructured":"Hirono, M. , Denis, C. S. , Richardson, G. P. & Gillespie, P. G . Hair cells require phosphatidylinositol 4,5-bisphosphate for mechanical transduction and adaptation. Neuron 44, 309\u2013320.","DOI":"10.1016\/j.neuron.2004.09.020"},{"key":"2026071404451070000_2025.04.01.646713v2.12","doi-asserted-by":"crossref","unstructured":"Effertz, T. , Becker, L. , Peng, A. W. & Ricci, A. J . Phosphoinositol-4,5-Bisphosphate Regulates Auditory Hair-Cell Mechanotransduction-Channel Pore Properties and Fast Adaptation. J Neurosci 37, 11632\u201311646.","DOI":"10.1523\/JNEUROSCI.1351-17.2017"},{"key":"2026071404451070000_2025.04.01.646713v2.13","doi-asserted-by":"crossref","unstructured":"Mburu, P. et al. Mutation analysis of the mouse myosin VIIA deafness gene. Genes Funct 1, 191\u2013203.","DOI":"10.1046\/j.1365-4624.1997.00020.x"},{"key":"2026071404451070000_2025.04.01.646713v2.14","doi-asserted-by":"crossref","unstructured":"Self, T. et al. Shaker-1 mutations reveal roles for myosin VIIA in both development and function of cochlear hair cells. Development 125, 557\u2013566.","DOI":"10.1242\/dev.125.4.557"},{"key":"2026071404451070000_2025.04.01.646713v2.15","doi-asserted-by":"crossref","unstructured":"Weil, D. et al. Defective myosin VIIA gene responsible for Usher syndrome type 1B. Nature 374, 60\u201361.","DOI":"10.1038\/374060a0"},{"key":"2026071404451070000_2025.04.01.646713v2.16","doi-asserted-by":"crossref","unstructured":"Weil, D. et al. The autosomal recessive isolated deafness, DFN B2, and the Usher 1B syndrome are allelic defects of the myosin-VIIA gene. Nat Genet 16, 191-193.","DOI":"10.1038\/ng0697-191"},{"key":"2026071404451070000_2025.04.01.646713v2.17","doi-asserted-by":"crossref","unstructured":"Liu, X. Z. et al. Mutations in the myosin VIIA gene cause non-syndromic recessive deafness. Nat Genet 16, 188\u2013190.","DOI":"10.1038\/ng0697-188"},{"key":"2026071404451070000_2025.04.01.646713v2.18","doi-asserted-by":"crossref","unstructured":"Grati, M. & Kachar, B . Myosin VIIa and sans localization at stereocilia upper tip-link density implicates these Usher syndrome proteins in mechanotransduction. Proc Natl Acad Sci U S A 108, 11476\u201311481.","DOI":"10.1073\/pnas.1104161108"},{"key":"2026071404451070000_2025.04.01.646713v2.19","doi-asserted-by":"crossref","unstructured":"Li, S. et al. Myosin-VIIa is expressed in multiple isoforms and essential for tensioning the hair cell mechanotransduction complex. Nat Commun 11, 2066.","DOI":"10.1038\/s41467-020-15936-z"},{"key":"2026071404451070000_2025.04.01.646713v2.20","doi-asserted-by":"crossref","unstructured":"Li, S. et al. A regulatory axis for tonotopic MYO7A expression in cochlear hair cells. Proc Natl Acad Sci U S A 123, e2519742123.","DOI":"10.1073\/pnas.2519742123"},{"key":"2026071404451070000_2025.04.01.646713v2.21","unstructured":"Li, S. et al. Tonotopic specialization of MYO7A isoforms in auditory hair cells. Nat Commun."},{"key":"2026071404451070000_2025.04.01.646713v2.22","doi-asserted-by":"crossref","unstructured":"Mecca, A. A. , Caprara, G. A. & Peng, A. W . cAMP and voltage modulate rat auditory mechanotransduction by decreasing the stiffness of gating springs. Proc Natl Acad Sci U S A 119, e2107567119.","DOI":"10.1073\/pnas.2107567119"},{"key":"2026071404451070000_2025.04.01.646713v2.23","doi-asserted-by":"crossref","unstructured":"Falkenburger, B. H. , Jensen, J. B. , Dickson, E. J. , Suh, B. C. & Hille, B . Phosphoinositides: lipid regulators of membrane proteins. J Physiol 588, 3179\u20133185.","DOI":"10.1113\/jphysiol.2010.192153"},{"key":"2026071404451070000_2025.04.01.646713v2.24","doi-asserted-by":"crossref","unstructured":"Hille, B. , Dickson, E. J. , Kruse, M. , Vivas, O. & Suh, B. C . Phosphoinositides regulate ion channels. Biochim Biophys Acta 1851, 844\u2013856.","DOI":"10.1016\/j.bbalip.2014.09.010"},{"key":"2026071404451070000_2025.04.01.646713v2.25","doi-asserted-by":"crossref","unstructured":"Rohacs, T . Phosphoinositide Regulation of TRP Channels: A Functional Overview in the Structural Era. Annu Rev Physiol 86, 329\u2013355.","DOI":"10.1146\/annurev-physiol-042022-013956"},{"key":"2026071404451070000_2025.04.01.646713v2.26","doi-asserted-by":"crossref","unstructured":"Cunningham, C. L. et al. TMIE Defines Pore and Gating Properties of the Mechanotransduction Channel of Mammalian Cochlear Hair Cells. Neuron 107, 126\u2013143.","DOI":"10.1016\/j.neuron.2020.03.033"},{"key":"2026071404451070000_2025.04.01.646713v2.27","doi-asserted-by":"crossref","unstructured":"Caprara, G. A. , Mecca, A. A. , Wang, Y. , Ricci, A. J. & Peng, A. W . Hair Bundle Stimulation Mode Modifies Manifestations of Mechanotransduction Adaptation. J Neurosci 39, 9098\u20139106.","DOI":"10.1523\/JNEUROSCI.1408-19.2019"},{"key":"2026071404451070000_2025.04.01.646713v2.28","doi-asserted-by":"crossref","unstructured":"Fettiplace, R. & Kim, K. X . The Physiology of Mechanoelectrical Transduction Channels in Hearing. Physiological reviews 94, 951\u2013986.","DOI":"10.1152\/physrev.00038.2013"},{"key":"2026071404451070000_2025.04.01.646713v2.29","doi-asserted-by":"crossref","unstructured":"Gillespie, P. G. & Cyr, J. L . Myosin-1c, the hair cell\u2019s adaptation motor. Annu Rev Physiol 66, 521\u2013545.","DOI":"10.1146\/annurev.physiol.66.032102.112842"},{"key":"2026071404451070000_2025.04.01.646713v2.30","doi-asserted-by":"crossref","unstructured":"Hokanson, D. E. & Ostap, E. M. Myo1c binds tightly and specifically to phosphatidylinositol 4,5-bisphosphate and inositol 1,4,5-trisphosphate. Proc Natl Acad Sci U S A 103, 3118\u20133123.","DOI":"10.1073\/pnas.0505685103"},{"key":"2026071404451070000_2025.04.01.646713v2.31","doi-asserted-by":"crossref","unstructured":"Phillips, K. R. , Tong, S. , Goodyear, R. , Richardson, G. P. & Cyr, J. L . Stereociliary myosin-1c receptors are sensitive to calcium chelation and absent from cadherin 23 mutant mice. J Neurosci 26, 10777\u201310788.","DOI":"10.1523\/JNEUROSCI.1847-06.2006"},{"key":"2026071404451070000_2025.04.01.646713v2.32","doi-asserted-by":"crossref","unstructured":"Zhao, B. et al. TMIE is an essential component of the mechanotransduction machinery of cochlear hair cells. Neuron 84, 954\u2013967.","DOI":"10.1016\/j.neuron.2014.10.041"},{"key":"2026071404451070000_2025.04.01.646713v2.33","doi-asserted-by":"crossref","unstructured":"Peng, A. W. , Effertz, T. & Ricci, A. J . Adaptation of mammalian auditory hair cell mechanotransduction is independent of calcium entry. Neuron 80, 960\u2013972.","DOI":"10.1016\/j.neuron.2013.08.025"},{"key":"2026071404451070000_2025.04.01.646713v2.34","doi-asserted-by":"crossref","unstructured":"Peng, A. W. , Gnanasambandam, R. , Sachs, F. & Ricci, A. J . Adaptation Independent Modulation of Auditory Hair Cell Mechanotransduction Channel Open Probability Implicates a Role for the Lipid Bilayer. J Neurosci 36, 2945\u20132956.","DOI":"10.1523\/JNEUROSCI.3011-15.2016"},{"key":"2026071404451070000_2025.04.01.646713v2.35","doi-asserted-by":"crossref","unstructured":"Assad, J. A. , Shepherd, G. M. & Corey, D. P . Tip-link integrity and mechanical transduction in vertebrate hair cells. Neuron 7, 985\u2013994.","DOI":"10.1016\/0896-6273(91)90343-X"},{"key":"2026071404451070000_2025.04.01.646713v2.36","doi-asserted-by":"crossref","unstructured":"Indzhykulian, A. A. et al. Molecular remodeling of tip links underlies mechanosensory regeneration in auditory hair cells. PLoS Biol 11, e1001583.","DOI":"10.1371\/journal.pbio.1001583"},{"key":"2026071404451070000_2025.04.01.646713v2.37","doi-asserted-by":"crossref","unstructured":"Tobin, M. , Chaiyasitdhi, A. , Michel, V. , Michalski, N. & Martin, P . Stiffness and tension gradients of the hair cell\u2019s tip-link complex in the mammalian cochlea. Elife 8.","DOI":"10.7554\/eLife.43473"},{"key":"2026071404451070000_2025.04.01.646713v2.38","doi-asserted-by":"crossref","unstructured":"Kawashima, Y. et al. Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes. J Clin Invest 121, 4796\u20134809.","DOI":"10.1172\/JCI60405"},{"key":"2026071404451070000_2025.04.01.646713v2.39","doi-asserted-by":"crossref","unstructured":"Giese, A. P. J. et al. CIB2 interacts with TMC1 and TMC2 and is essential for mechanotransduction in auditory hair cells. Nat Commun 8, 43.","DOI":"10.1038\/s41467-017-00061-1"},{"key":"2026071404451070000_2025.04.01.646713v2.40","doi-asserted-by":"crossref","unstructured":"Michel, V. et al. CIB2, defective in isolated deafness, is key for auditory hair cell mechanotransduction and survival. EMBO Mol Med 9, 1711\u20131731.","DOI":"10.15252\/emmm.201708087"},{"key":"2026071404451070000_2025.04.01.646713v2.41","doi-asserted-by":"crossref","unstructured":"Wang, Y. et al. Loss of CIB2 Causes Profound Hearing Loss and Abolishes Mechanoelectrical Transduction in Mice. Front Mol Neurosci 10, 401.","DOI":"10.3389\/fnmol.2017.00401"},{"key":"2026071404451070000_2025.04.01.646713v2.42","doi-asserted-by":"crossref","unstructured":"Jeong, H. et al. Structures of the TMC-1 complex illuminate mechanosensory transduction. Nature 610, 796\u2013803.","DOI":"10.1038\/s41586-022-05314-8"},{"key":"2026071404451070000_2025.04.01.646713v2.43","doi-asserted-by":"crossref","unstructured":"De-la-Torre, P. et al. Identification of druggable binding sites and small molecules as modulators of TMC1. Commun Biol 8, 742.","DOI":"10.1038\/s42003-025-07943-x"},{"key":"2026071404451070000_2025.04.01.646713v2.44","doi-asserted-by":"crossref","unstructured":"Beurg, M. , Fettiplace, R. , Nam, J. H. & Ricci, A. J . Localization of inner hair cell mechanotransducer channels using high-speed calcium imaging. Nat Neurosci 12, 553\u2013558.","DOI":"10.1038\/nn.2295"},{"key":"2026071404451070000_2025.04.01.646713v2.45","doi-asserted-by":"crossref","unstructured":"Gillespie, P. G. & Muller, U . Mechanotransduction by hair cells: models, molecules, and mechanisms. Cell 139, 33\u201344.","DOI":"10.1016\/j.cell.2009.09.010"},{"key":"2026071404451070000_2025.04.01.646713v2.46","doi-asserted-by":"crossref","unstructured":"Beurg, M. et al. Variable number of TMC1-dependent mechanotransducer channels underlie tonotopic conductance gradients in the cochlea. Nat Commun 9, 2185.","DOI":"10.1038\/s41467-018-04589-8"},{"key":"2026071404451070000_2025.04.01.646713v2.47","doi-asserted-by":"crossref","unstructured":"Pan, B. et al. TMC1 and TMC2 are components of the mechanotransduction channel in hair cells of the mammalian inner ear. Neuron 79, 504\u2013515.","DOI":"10.1016\/j.neuron.2013.06.019"},{"key":"2026071404451070000_2025.04.01.646713v2.48","doi-asserted-by":"crossref","unstructured":"Gillespie, P. G. , Wagner, M. C. & Hudspeth, A. J . Identification of a 120 kd hair-bundle myosin located near stereociliary tips. Neuron 11, 581\u2013594.","DOI":"10.1016\/0896-6273(93)90071-X"},{"key":"2026071404451070000_2025.04.01.646713v2.49","doi-asserted-by":"crossref","unstructured":"Underhill, A. et al. MYO7A is required for the functional integrity of the mechanoelectrical transduction complex in hair cells of the adult cochlea. Proc Natl Acad Sci U S A 122, e2414707122.","DOI":"10.1073\/pnas.2414707122"},{"key":"2026071404451070000_2025.04.01.646713v2.50","doi-asserted-by":"crossref","unstructured":"Howard, J. & Hudspeth, A. J . Compliance of the hair bundle associated with gating of mechanoelectrical transduction channels in the bullfrog\u2019s saccular hair cell. Neuron 1, 189\u2013199.","DOI":"10.1016\/0896-6273(88)90139-0"},{"key":"2026071404451070000_2025.04.01.646713v2.51","doi-asserted-by":"crossref","unstructured":"Gianoli, F. , Risler, T. & Kozlov, A. S . Lipid bilayer mediates ion-channel cooperativity in a model of hair-cell mechanotransduction. Proc Natl Acad Sci U S A 114, E11010\u2013E11019.","DOI":"10.1073\/pnas.1713135114"},{"key":"2026071404451070000_2025.04.01.646713v2.52","doi-asserted-by":"crossref","unstructured":"Ballesteros, A. & Swartz, K. J . Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing. Sci Adv 8, eabm5550.","DOI":"10.1126\/sciadv.abm5550"},{"key":"2026071404451070000_2025.04.01.646713v2.53","unstructured":"Sam George, S. & Ricci, A. J. Auditory Hair Cell Mechanotransduction Channels Dynamically Shape the Mechanical Properties of Their Membrane Environment. Adv Sci (Weinh ), e08268."},{"key":"2026071404451070000_2025.04.01.646713v2.54","doi-asserted-by":"crossref","unstructured":"Jia, Y. et al. TMC1 and TMC2 Proteins Are Pore-Forming Subunits of Mechanosensitive Ion Channels. Neuron 105, 310\u2013321 e313.","DOI":"10.1016\/j.neuron.2019.10.017"},{"key":"2026071404451070000_2025.04.01.646713v2.55","unstructured":"Fu, S. , Pan, X. , Lu, M. , Dong, J. & Yan, Z . Human TMC1 and TMC2 are mechanically gated ion channels. Neuron."},{"key":"2026071404451070000_2025.04.01.646713v2.56","doi-asserted-by":"crossref","unstructured":"Chen, Y. et al. Ectopic mouse TMC1 and TMC2 alone form mechanosensitive channels that are potently modulated by TMIE. Proc Natl Acad Sci U S A 122, e2403141122.","DOI":"10.1073\/pnas.2403141122"},{"key":"2026071404451070000_2025.04.01.646713v2.57","doi-asserted-by":"crossref","unstructured":"Qiu, X. , Liang, X. , Llongueras, J. P. , Cunningham, C. & Muller, U . The tetraspan LHFPL5 is critical to establish maximal force sensitivity of the mechanotransduction channel of cochlear hair cells. Cell Rep 42, 112245.","DOI":"10.1016\/j.celrep.2023.112245"},{"key":"2026071404451070000_2025.04.01.646713v2.58","doi-asserted-by":"crossref","unstructured":"Beurg, M. , Schwalbach, E. T. & Fettiplace, R . LHFPL5 is a key element in force transmission from the tip link to the hair cell mechanotransducer channel. Proc Natl Acad Sci U S A 121, e2318270121.","DOI":"10.1073\/pnas.2318270121"},{"key":"2026071404451070000_2025.04.01.646713v2.59","doi-asserted-by":"crossref","unstructured":"Qiu, X. , Llongueras, J. P. , Yin, L. , Cunningham, C. & Muller, U . LHFPL5 is required for maximal activation of the mechanotransduction channel in cochlear hair cells. Proc Natl Acad Sci U S A 122, e2505627122.","DOI":"10.1073\/pnas.2505627122"},{"key":"2026071404451070000_2025.04.01.646713v2.60","doi-asserted-by":"crossref","unstructured":"Martinac, B. & Kung, C . The force-from-lipid principle and its origin, a \u2019what is true for E. coli is true for the elephant\u2019 refrain. J Neurogenet 36, 44\u201354.","DOI":"10.1080\/01677063.2022.2097674"},{"key":"2026071404451070000_2025.04.01.646713v2.61","doi-asserted-by":"crossref","unstructured":"Le, S. C. , Jia, Z. , Chen, J. & Yang, H . Molecular basis of PIP2-dependent regulation of the Ca(2+)-activated chloride channel TMEM16A. Nat Commun 10, 3769.","DOI":"10.1038\/s41467-019-11784-8"},{"key":"2026071404451070000_2025.04.01.646713v2.62","doi-asserted-by":"crossref","unstructured":"Tembo, M. , Wozniak, K. L. , Bainbridge, R. E. & Carlson, A. E . Phosphatidylinositol 4,5-bisphosphate (PIP(2)) and Ca(2+) are both required to open the Cl(-) channel TMEM16A. J Biol Chem 294, 12556\u201312564.","DOI":"10.1074\/jbc.RA118.007128"},{"key":"2026071404451070000_2025.04.01.646713v2.63","doi-asserted-by":"crossref","unstructured":"Yu, K. , Jiang, T. , Cui, Y. , Tajkhorshid, E. & Hartzell, H. C . A network of phosphatidylinositol 4,5-bisphosphate binding sites regulates gating of the Ca(2+)-activated Cl(-) channel ANO1 (TMEM16A). Proc Natl Acad Sci U S A 116, 19952\u201319962.","DOI":"10.1073\/pnas.1904012116"},{"key":"2026071404451070000_2025.04.01.646713v2.64","doi-asserted-by":"crossref","unstructured":"Ballesteros, A. , Fenollar-Ferrer, C. & Swartz, K. J . Structural relationship between the putative hair cell mechanotransduction channel TMC1 and TMEM16 proteins. Elife 7.","DOI":"10.7554\/eLife.38433"},{"key":"2026071404451070000_2025.04.01.646713v2.65","doi-asserted-by":"crossref","unstructured":"Pan, B. et al. TMC1 Forms the Pore of Mechanosensory Transduction Channels in Vertebrate Inner Ear Hair Cells. Neuron 99, 736\u2013753 e736.","DOI":"10.1016\/j.neuron.2018.07.033"},{"key":"2026071404451070000_2025.04.01.646713v2.66","doi-asserted-by":"crossref","unstructured":"Clark, S. , Jeong, H. , Posert, R. , Goehring, A. & Gouaux, E . The structure of the Caenorhabditis elegans TMC-2 complex suggests roles of lipid-mediated subunit contacts in mechanosensory transduction. Proc Natl Acad Sci U S A 121, e2314096121.","DOI":"10.1073\/pnas.2314096121"},{"key":"2026071404451070000_2025.04.01.646713v2.67","doi-asserted-by":"crossref","unstructured":"Peng, A. W. et al. Fluid Jet Stimulation of Auditory Hair Bundles Reveal Spatial Non-uniformities and Two Viscoelastic-Like Mechanisms. Front Cell Dev Biol 9, 725101.","DOI":"10.3389\/fcell.2021.725101"},{"key":"2026071404451070000_2025.04.01.646713v2.68","unstructured":"Edelstein, A. D. et al. Advanced methods of microscope control using muManager software. J Biol Methods 1."},{"key":"2026071404451070000_2025.04.01.646713v2.69","unstructured":"Lee, H. et al. TMC1 and TMC2 are cholesterol-dependent scramblases that regulate membrane homeostasis in auditory hair cells. bioRxiv."},{"key":"2026071404451070000_2025.04.01.646713v2.70","doi-asserted-by":"crossref","unstructured":"Lupyan, D. , Mezei, M. , Logothetis, D. E. & Osman, R . A molecular dynamics investigation of lipid bilayer perturbation by PIP2. Biophys J 98, 240\u2013247.","DOI":"10.1016\/j.bpj.2009.09.063"},{"key":"2026071404451070000_2025.04.01.646713v2.71","doi-asserted-by":"crossref","unstructured":"Lee, K. I. , Im, W. & Pastor, R. W . Langevin dynamics simulations of charged model phosphatidylinositol lipids in the presence of diffusion barriers: toward an atomic level understanding of corralling of PIP2 by protein fences in biological membranes. BMC Biophys 7, 13.","DOI":"10.1186\/s13628-014-0013-3"},{"key":"2026071404451070000_2025.04.01.646713v2.72","doi-asserted-by":"crossref","unstructured":"Ingolfsson, H. I. et al. Lipid organization of the plasma membrane. J Am Chem Soc 136, 14554\u201314559.","DOI":"10.1021\/ja507832e"},{"key":"2026071404451070000_2025.04.01.646713v2.73","doi-asserted-by":"crossref","unstructured":"Huang, J. & MacKerell, A. D., Jr . CHARMM36 all-atom additive protein force field: validation based on comparison to NMR data. J Comput Chem 34, 2135\u20132145.","DOI":"10.1002\/jcc.23354"},{"key":"2026071404451070000_2025.04.01.646713v2.74","doi-asserted-by":"crossref","unstructured":"Johnson, S. L. , Beurg, M. , Marcotti, W. & Fettiplace, R . Prestin-driven cochlear amplification is not limited by the outer hair cell membrane time constant. Neuron 70, 1143\u20131154.","DOI":"10.1016\/j.neuron.2011.04.024"},{"key":"2026071404451070000_2025.04.01.646713v2.75","unstructured":"Walujkar, S. et al. <em>In Silico<\/em> Electrophysiology of Inner-Ear Mechanotransduction Channel TMC1 Models. bioRxiv."},{"key":"2026071404451070000_2025.04.01.646713v2.76","doi-asserted-by":"crossref","unstructured":"Kutzner, C. , Grubmuller, H. , de Groot, B. L. & Zachariae, U . Computational electrophysiology: the molecular dynamics of ion channel permeation and selectivity in atomistic detail. Biophys J 101, 809\u2013817.","DOI":"10.1016\/j.bpj.2011.06.010"},{"key":"2026071404451070000_2025.04.01.646713v2.77","doi-asserted-by":"crossref","unstructured":"Aksimentiev, A. & Schulten, K . Imaging alpha-hemolysin with molecular dynamics: ionic conductance, osmotic permeability, and the electrostatic potential map. Biophys J 88, 3745\u20133761.","DOI":"10.1529\/biophysj.104.058727"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.01.646713","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T11:45:26Z","timestamp":1784029526000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.04.01.646713"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,6]]},"references-count":77,"URL":"https:\/\/doi.org\/10.1101\/2025.04.01.646713","relation":{},"subject":[],"published":{"date-parts":[[2025,4,6]]},"subtype":"preprint"}}