Altered voltage-dependence of slowly activating chloride-proton antiport by late endosomal ClC-6 explains distinct neurological disorders.
Kufs disease
anion transport
endosome
organellar homeostasis
vesicular CLC
Journal
The Journal of physiology
ISSN: 1469-7793
Titre abrégé: J Physiol
Pays: England
ID NLM: 0266262
Informations de publication
Date de publication:
05 2022
05 2022
Historique:
received:
14
12
2021
accepted:
01
03
2022
pubmed:
10
3
2022
medline:
3
5
2022
entrez:
9
3
2022
Statut:
ppublish
Résumé
ClC-6 is an intracellularly localised member of the CLC family of chloride transport proteins. It presumably functions in the endolysosomal compartment as a chloride-proton 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-type ClC-6 function obscures clear mechanistic insight into disease aetiology. Here, high-resolution 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-type ClC-6 activation and transport require depolarisation to voltages beyond 140 mV. Mutant Y553C associated with early-onset neurodegeneration exerts gain-of-function by shifting the half-maximal 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-onset lysosomal storage disease, can explain loss-of-function leading to disease. KEY POINTS: Ionic composition and pH within intracellular compartments, such as endolysosomes, rely on the activity of chloride/proton transporters including ClC-6. Distinct CLCN6 mutations were previously found in individuals with neurodegenerative disease, and also putatively associated with neuronal ceroid lipofuscinosis. Limited knowledge of wild-type ClC-6 transport function impedes understanding of mechanisms underlying these conditions. We resolved transient and transport currents that permit measurement of voltage- and pH-dependences, as well as kinetics, for wild-type and disease-associated mutant ClC-6s. These findings define wild-type ClC-6 function robustly, and reveal how alterations of the slow activation gating of the transporter cause different kinds of neurological diseases.
Substances chimiques
Chloride Channels
0
Chlorides
0
Protons
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2147-2164Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.
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