{"id":19193,"date":"2026-02-27T16:27:05","date_gmt":"2026-02-27T14:27:05","guid":{"rendered":"https:\/\/www.nanion.de\/?post_type=resource_library&#038;p=19193"},"modified":"2026-02-27T16:27:05","modified_gmt":"2026-02-27T14:27:05","slug":"2026-activation-of-tmem175-lysosomal-ion-channels-by-cyslt1-receptor-antagonists","status":"publish","type":"resource_library","link":"https:\/\/nanion.com\/ja\/resource_library\/2026-activation-of-tmem175-lysosomal-ion-channels-by-cyslt1-receptor-antagonists\/","title":{"rendered":"2026 &#8211; Activation of TMEM175 lysosomal ion channels by CysLT1 receptor antagonists"},"content":{"rendered":"<p>TMEM175 is an AKT-activated lysosomal potassium- and proton-permeable channel that functions to dissipate voltage and pH gradients generated by the V-type H<sup>+<\/sup>-ATPase. Loss-of-function (LOF) variants in TMEM175 have been identified as genetic risk factors for Parkinson\u2019s disease (PD), highlighting the potential of small-molecule activators as a novel therapeutic strategy for this disease. We developed a high-throughput screening assay using HEK-293 cells stably overexpressing TMEM175 at the cell surface and screened 960 FDA-approved drugs for TMEM175 potentiators. The screen identified 71 activators, including the cysteinyl leukotriene 1 receptor (CysLT1R) antagonists, pranlukast and montelukast. Because HEK-293 cells lack CysLT1R expression, we suspected these drugs may be direct channel activators. Fluorescence and automated patch clamp assays were used to evaluate the dose-dependency of pranlukast, montelukast, zafirlukast, and the known TMEM175 activator, DCPIB. These experiments revealed rank-order potencies and efficacies of DCPIB ~ zafirlukast &gt; montelukast &gt;&gt; pranlukast. DCPIB, zafirlukast, and pranlukast activated TMEM175 independently of AKT activation, whereas the AKT inhibitor MK2206 partially inhibited montelukast-dependent TMEM175 activation. Computer modeling revealed a conformation-dependent solvent-accessible cavity near T119 and H449 that could participate in drug-induced activation, prompting us to examine these sites with mutagenesis. Not only did T119A and H449A mutations decrease apparent potencies of DCPIB, zafirlukast, and montelukast, but the T119A mutation produced a constitutively open channel phenotype. This study adds zafirlukast to the short list of moderately potent TMEM175 activators and identifies a region of the channel that contributes to activation gating.<\/p>\n","protected":false},"featured_media":0,"template":"","products_tags":[42],"resource_type":[75],"application_areas":[50,53,76],"therapeutic_areas":[143,403],"target_categories":[335],"target_families":[489],"targets":[399],"resource_keyword":[],"class_list":["post-19193","resource_library","type-resource_library","status-publish","hentry","products_tags-syncropatch-384","resource_type-publication","application_areas-ion-channels","application_areas-assay-development-and-validation","application_areas-drug-discovery","therapeutic_areas-assay-development-and-validation","therapeutic_areas-lysosomal-diseases","target_categories-intracellular-regulated-ion-channels","target_families-k-selective-ion-channel","targets-tmem175"],"acf":[],"_links":{"self":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library\/19193","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_library"}],"about":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/types\/resource_library"}],"wp:attachment":[{"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/media?parent=19193"}],"wp:term":[{"taxonomy":"products_tags","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/products_tags?post=19193"},{"taxonomy":"resource_type","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_type?post=19193"},{"taxonomy":"application_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/application_areas?post=19193"},{"taxonomy":"therapeutic_areas","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/therapeutic_areas?post=19193"},{"taxonomy":"target_categories","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_categories?post=19193"},{"taxonomy":"target_families","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/target_families?post=19193"},{"taxonomy":"targets","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/targets?post=19193"},{"taxonomy":"resource_keyword","embeddable":true,"href":"https:\/\/nanion.com\/ja\/wp-json\/wp\/v2\/resource_keyword?post=19193"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}