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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,1,20]]},"abstract":"<jats:p>\n                    The lysosomal cation channel TMEM175 plays a key role in luminal pH homeostasis and lysosome function, with aberrant activity linked to Parkinson\u2019s disease. Although initially described as a K\n                    <jats:sup>+<\/jats:sup>\n                    -selective channel, TMEM175 exhibits substantial H\n                    <jats:sup>+<\/jats:sup>\n                    permeability. Here, we dissect complex changes affecting human TMEM175 conductance and ionic properties of TMEM175-mediated current in response to pH shifts on the luminal side of the protein. A drop in pH from 7.4 to 4.7 on the side equivalent to the lysosomal lumen triggers a sustained increase in TMEM175-mediated inward and outward currents, which is accompanied by a transient shift in the reversal potential (E\n                    <jats:sub>rev<\/jats:sub>\n                    ) toward the theoretical equilibrium voltage for H\n                    <jats:sup>+<\/jats:sup>\n                    , yet remaining ~100 mV below the expected value even in the absence of K\n                    <jats:sup>+<\/jats:sup>\n                    . This discrepancy, along with low sensitivity of E\n                    <jats:sub>rev<\/jats:sub>\n                    to the concentration gradient for K\n                    <jats:sup>+<\/jats:sup>\n                    , supports a model in which TMEM175-mediated H\n                    <jats:sup>+<\/jats:sup>\n                    flux rapidly collapses the lysosomal pH-gradient. Molecular dynamics simulations identify H57 as a key residue on the luminal side of the open channel, which forms intra- and intersubunit salt bridges with D279 and E282. Supporting the functional importance of these interactions, the TMEM175 mutant H57Y displayed reduced H\n                    <jats:sup>+<\/jats:sup>\n                    - and K\n                    <jats:sup>+<\/jats:sup>\n                    -conductance and a reduced H\n                    <jats:sup>+<\/jats:sup>\n                    \/K\n                    <jats:sup>+<\/jats:sup>\n                    selectivity in whole-cell and lysosomal electrophysiological analyses. Our findings contribute to a better understanding of TMEM175\u2019s complex electrophysiological properties, thereby expanding the possibilities of understanding the channel\u2019s function in lysosomal physiology and pathophysiology.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2503909123","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T16:45:23Z","timestamp":1768409123000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["Proton-selective conductance and gating of the lysosomal cation channel TMEM175"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9715-8717","authenticated-orcid":false,"given":"Tobias","family":"Schulze","sequence":"first","affiliation":[{"name":"Department of Biology, Membrane Biophysics, Technical University of Darmstadt","place":["Darmstadt, Germany"]},{"name":"Walther Straub Institute of Pharmacology and Toxicology, Endolysosomal Ion Channel Research, Faculty of Medicine, Ludwig-Maximilians-Universit\u00e4t","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-1532-4456","authenticated-orcid":false,"given":"Timon","family":"Sprave","sequence":"additional","affiliation":[{"name":"Department of Biology, Membrane Biophysics, Technical University of Darmstadt","place":["Darmstadt, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8500-514X","authenticated-orcid":false,"given":"Carolin","family":"Groebe","sequence":"additional","affiliation":[{"name":"Department of Biology, Membrane Biophysics, Technical University of Darmstadt","place":["Darmstadt, Germany"]},{"name":"Institute of Pathophysiology, Physiology and Pathophysiology of Cortical Neuronal Networks, Biomedical Research Centre, University Medical Center of the Johannes Gutenberg University","place":["Mainz, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Hendrik Krumbach","sequence":"additional","affiliation":[{"name":"Department of Biology, Computational Biology & Simulation, Technical University of Darmstadt","place":["Darmstadt, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6368-113X","authenticated-orcid":false,"given":"Magnus","family":"Behringer","sequence":"additional","affiliation":[{"name":"Department of Biology, Computational Biology & Simulation, Technical University of Darmstadt","place":["Darmstadt, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2419-3519","authenticated-orcid":false,"given":"Andre","family":"Bazzone","sequence":"additional","affiliation":[{"name":"Nanion Technologies","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7606-0871","authenticated-orcid":false,"given":"Rocco","family":"Zerlotti","sequence":"additional","affiliation":[{"name":"Nanion Technologies","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9731-2283","authenticated-orcid":false,"given":"Niels","family":"Fertig","sequence":"additional","affiliation":[{"name":"Nanion Technologies","place":["Munich, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3554-7538","authenticated-orcid":false,"given":"Mike","family":"Althaus","sequence":"additional","affiliation":[{"name":"Institute for Functional Gene Analytics, Department of Natural Sciences, Bonn-Rhein- Sieg University of Applied Sciences","place":["Rheinbach, 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