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Metabolic Energy Sensing by Mammalian CLC Anion/Proton Exchangers

Matthias Grieschat, Katharina Langschwager, Raul E. Guzman, Christoph Fahlke, View ORCID ProfileAlexi K. Alekov
doi: https://doi.org/10.1101/545368
Matthias Grieschat
1Institute of Neurophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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Katharina Langschwager
1Institute of Neurophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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Raul E. Guzman
2Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, Leo-Brandt-Straße, 52428 Jülich, Germany
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Christoph Fahlke
2Institute of Complex Systems, Zelluläre Biophysik (ICS-4), Forschungszentrum Jülich, Leo-Brandt-Straße, 52428 Jülich, Germany
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Alexi K. Alekov
1Institute of Neurophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
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  • ORCID record for Alexi K. Alekov
  • For correspondence: alexi.alekov@gmail.com
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Abstract

Mammalian CLC anion/proton exchangers control the pH and [Cl-] of the endolysosomal system, one of the major cellular nutrient uptake pathways. We explored the regulation of the vesicular transporters ClC-3, ClC-4, and ClC-5 by the adenylic system components ATP, ADP, and AMP. Using heterologous expression and whole-cell electrophysiology, we demonstrated that cytosolic ATP and ADP but not AMP and Mg2+-free ADP enhance CLC ion transport via binding to the protein C-terminal CBS domains. Biophysical investigations revealed that the effects depend on the delivery of intracellular protons into the CLC transport machinery and result from modified voltage-dependence and altered probability that CLC proteins undergo silent non-transporting cycles. Our findings demonstrate that the CLC CBS domains are able to serve as energy sensors by detecting changes in the cytosolic ATP/ADP/AMP equilibrium. The adenine nucleotide regulation of vesicular Cl-/H+ exchange creates a link between the activity of the endolysosomal system and the cellular metabolic state.

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  • Competing Interests The authors declare that no competing interests exist.

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Posted February 08, 2019.
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Metabolic Energy Sensing by Mammalian CLC Anion/Proton Exchangers
Matthias Grieschat, Katharina Langschwager, Raul E. Guzman, Christoph Fahlke, Alexi K. Alekov
bioRxiv 545368; doi: https://doi.org/10.1101/545368
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Metabolic Energy Sensing by Mammalian CLC Anion/Proton Exchangers
Matthias Grieschat, Katharina Langschwager, Raul E. Guzman, Christoph Fahlke, Alexi K. Alekov
bioRxiv 545368; doi: https://doi.org/10.1101/545368

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