{"id":18789,"date":"2026-01-15T09:56:05","date_gmt":"2026-01-15T07:56:05","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=18789"},"modified":"2026-01-15T09:56:05","modified_gmt":"2026-01-15T07:56:05","slug":"2026-proton-selective-conductance-and-gating-of-the-lysosomal-cation-channel-tmem175","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/zh-hans\/resource_library\/2026-proton-selective-conductance-and-gating-of-the-lysosomal-cation-channel-tmem175\/","title":{"rendered":"2026 &#8211; Proton-selective conductance and gating of the lysosomal cation channel TMEM175"},"content":{"rendered":"<p>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<sup>+<\/sup>-selective channel, TMEM175 exhibits substantial H<sup>+<\/sup>\u00a0permeability. 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<sub>rev<\/sub>) toward the theoretical equilibrium voltage for H<sup>+<\/sup>, yet remaining ~100 mV below the expected value even in the absence of K<sup>+<\/sup>. This discrepancy, along with low sensitivity of E<sub>rev<\/sub>\u00a0to the concentration gradient for K<sup>+<\/sup>, supports a model in which TMEM175-mediated H<sup>+<\/sup>\u00a0flux 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<sup>+<\/sup>&#8211; and K<sup>+<\/sup>-conductance and a reduced H<sup>+<\/sup>\/K<sup>+<\/sup>\u00a0selectivity 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.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[36],"resource_type":[75],"application_areas":[50,76,108],"therapeutic_areas":[143,403],"target_categories":[338,60],"target_families":[489],"targets":[399],"resource_keyword":[],"class_list":["post-18789","resource_library","type-resource_library","status-publish","hentry","products_tags-surfe2r-n1","resource_type-publication","application_areas-ion-channels","application_areas-drug-discovery","application_areas-transporters","therapeutic_areas-assay-development-and-validation","therapeutic_areas-lysosomal-diseases","target_categories-other-ion-channels","target_categories-transporters","target_families-k-selective-ion-channel","targets-tmem175"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library\/18789","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/media?parent=18789"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/products_tags?post=18789"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_type?post=18789"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/application_areas?post=18789"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/therapeutic_areas?post=18789"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_categories?post=18789"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/target_families?post=18789"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/targets?post=18789"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/zh-hans\/wp-json\/wp\/v2\/resource_keyword?post=18789"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}