Proton-Activated Chloride Channel: Physiology and Disease

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IMR Press / FBL / Volume 28 / Issue 1 / DOI: 10.31083/j.fbl2801011

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Proton-Activated Chloride Channel: Physiology and Disease

Fanglin Peng^1,2, Yi Wu^3,4, Xianping Dong^5,*, Peng Huang^2,*

¹ School of Health Science and Engineering, University of Shanghai for Science and Technology, 200093 Shanghai, China

² Chongming Hospital Affiliated to Shanghai University of Medicine and Health Sciences, 202150 Shanghai, China

³ Collaborative Innovation Center for Biomedicine, Shanghai University of Medicine and Health Sciences, 201318 Shanghai, China

⁴ School of Pharmacy, Shanghai University of Medicine and Health Sciences, 201318 Shanghai, China

⁵ Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada

^*Correspondence: xpdong@dal.ca (Xianping Dong); huangp_15@sumhs.edu.cn (Peng Huang)
Academic Editors: Kavindra Kumar Kesari and Dhruv Kumar

Front. Biosci. (Landmark Ed) 2023, 28(1), 11; https://doi.org/10.31083/j.fbl2801011

Submitted: 1 October 2022 | Revised: 26 November 2022 | Accepted: 28 November 2022 | Published: 16 January 2023

(This article belongs to the Special Issue Autophagy and Metabolism in Cancer)

Copyright: © 2023 The Author(s). Published by IMR Press.

This is an open access article under the CC BY 4.0 license.

Abstract

The maintenance of intracellular and extracellular pH relies on multiple ion transporters/channels. Proton-activated chloride channel (PAC) precisely regulates extracellular and early/late endosomal pH by transporting chloride ion (Cl ${}^{-}$ ) across membranes and has been shown to be implicated in pH imbalance under hypoxic conditions, such as the acidic microenvironments of cancer and ischemia. In this article, the phenotypic characteristics, molecular mechanisms, physiology of PAC and its role in cancer, ischemic stroke and hypoxia will be discussed in order to provide some clues for developing potential therapeutic strategies.

Keywords

proton-activated chloride channel

endosomes

tissue acidosis

hypothermia

Funding

20204Y0379/Shanghai Municipal Health Commission Foundation grant to Y.W.

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Fig. 1.

Channels to maintain pH in endosomes. V-ATPase maintains luminal pH by inducing the influx of proton. CLC 2Cl ${}^{-}$ /H ${}^{+}$ exchangers (especially CLC-3-CLC-6) facilitate endosomal acidification by increasing luminal Cl ${}^{-}$ level and providing the electric shunt for proton pumping by the V-ATPase. Intracellular domains of NHE1 regulate endosomal pH by protons efflux in exchange for Na ${}^{+}$ and K ${}^{+}$ . Once the endosomal pH reaches the activation threshold of PAC, PAC activates and prevents endosomes from over-acidification by mediating the efflux of Cl ${}^{-}$ . The above channels/exchangers cooperate and precisely regulate the homeostasis of endosomal pH.

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Front. Biosci. (Landmark Ed) Print ISSN 2768-6701 Electronic ISSN 2768-6698