{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:53:47Z","timestamp":1784076827065,"version":"3.55.0"},"reference-count":41,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2022,3,30]],"date-time":"2022-03-30T00:00:00Z","timestamp":1648598400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["# IG 21558"],"award-info":[{"award-number":["# IG 21558"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>ClC\u20106 is an intracellularly localised member of the CLC family of chloride transport proteins. It presumably functions in the endolysosomal compartment as a chloride\u2010proton antiporter, despite a paucity of biophysical studies in direct support. Observations of lysosomal storage disease, as well as neurodegenerative disorders, emerge with its disruption by knockout or mutation, respectively. An incomplete understanding of wild\u2010type ClC\u20106 function obscures clear mechanistic insight into disease aetiology. Here, high\u2010resolution recording protocols that incorporate extreme voltage pulses permit detailed biophysical measurement and analysis of transient capacitive, as well as ionic transport currents. This approach reveals that wild\u2010type ClC\u20106 activation and transport require depolarisation to voltages beyond 140\u00a0mV. Mutant Y553C associated with early\u2010onset neurodegeneration exerts gain\u2010of\u2010function by shifting the half\u2010maximal voltage for activation to less depolarised voltages. Moreover, we show that the E267A proton glutamate mutant conserves transport currents, albeit reduced. Lastly, the positive shift in activation voltage shown by V580M, a mutant identified in a patient with late\u2010onset lysosomal storage disease, can explain loss\u2010of\u2010function leading to disease.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Ionic composition and pH within intracellular compartments, such as endolysosomes, rely on the activity of chloride\/proton transporters including ClC\u20106.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Distinct <jats:italic>CLCN6<\/jats:italic> mutations were previously found in individuals with neurodegenerative disease, and also putatively associated with neuronal ceroid lipofuscinosis.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Limited knowledge of wild\u2010type ClC\u20106 transport function impedes understanding of mechanisms underlying these conditions.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We resolved transient and transport currents that permit measurement of voltage\u2010 and pH\u2010dependences, as well as kinetics, for wild\u2010type and disease\u2010associated mutant ClC\u20106s.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These findings define wild\u2010type ClC\u20106 function robustly, and reveal how alterations of the slow activation gating of the transporter cause different kinds of neurological diseases.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp282737","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T12:23:21Z","timestamp":1646828601000},"page":"2147-2164","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Altered voltage\u2010dependence of slowly activating chloride\u2010proton antiport by late endosomal ClC\u20106 explains distinct neurological 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