{"id":13442,"date":"2023-08-14T10:35:00","date_gmt":"2023-08-14T10:35:00","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/?post_type=journal-paper&p=13442"},"modified":"2026-01-30T10:45:26","modified_gmt":"2026-01-30T10:45:26","slug":"a-comparative-study-on-the-lysosomal-cation-channel-tmem175-using-automated-whole-cell-patch-clamp-lysosomal-patch-clamp-and-solid-supported-membrane-based-electrophysiology-functional-characteriza","status":"publish","type":"journal-paper","link":"https:\/\/www.sygnaturediscovery.com\/fr\/journal-paper\/a-comparative-study-on-the-lysosomal-cation-channel-tmem175-using-automated-whole-cell-patch-clamp-lysosomal-patch-clamp-and-solid-supported-membrane-based-electrophysiology-functional-characteriza\/","title":{"rendered":"A Comparative Study on the Lysosomal Cation Channel TMEM175 Using Automated Whole-Cell Patch-Clamp, Lysosomal Patch-Clamp, and Solid Supported Membrane-Based Electrophysiology: Functional Characterization and High-Throughput Screening Assay Development"},"content":{"rendered":"\n

Andre Bazzone, <\/a>Maria Barthmes, Cecilia George, Nina Brinkwirth, Rocco Zerlotti, Valentin Prinz, Kim Cole, S\u00f8ren Friis, Alexander Dickson<\/strong>, Simon Rice<\/strong>, Jongwon Lim, <\/a>May Fern Toh, <\/a>Milad Mohammadi, Davide Pau<\/strong>, David J. Stone, John J. Renger\u00a0and Niels Fertig<\/p>\n\n\n\n

Abstract<\/strong><\/p>\n\n\n\n

The lysosomal cation channel TMEM175 is a Parkinson\u2019s disease-related protein and a promising drug target. Unlike whole-cell automated patch-clamp (APC), lysosomal patch-clamp (LPC) facilitates physiological conditions, but is not yet suitable for high-throughput screening (HTS) applications. Here, we apply solid supported membrane-based electrophysiology (SSME), which enables both direct access to lysosomes and high-throughput electrophysiological recordings. In SSME, ion translocation mediated by TMEM175 is stimulated using a concentration gradient at a resting potential of 0 mV. The concentration-dependent K+<\/sup> response exhibited an I\/c curve with two distinct slopes, indicating the existence of two conducting states. We measured H+<\/sup> fluxes with a permeability ratio of PH<\/sub>\/PK<\/sub> = 48,500, which matches literature findings from patch-clamp studies, validating the SSME approach. Additionally, TMEM175 displayed a high pH dependence. Decreasing cytosolic pH inhibited both K+<\/sup> and H+<\/sup> conductivity of TMEM175. Conversely, lysosomal pH and pH gradients did not have major effects on TMEM175. Finally, we developed HTS assays for drug screening and evaluated tool compounds (4-AP, Zn as inhibitors; DCPIB, arachidonic acid, SC-79 as enhancers) using SSME and APC. Additionally, we recorded EC50<\/sub> data for eight blinded TMEM175 enhancers and compared the results across all three assay technologies, including LPC, discussing their advantages and disadvantages.<\/p>\n\n\n\n

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