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ClC-2 Chloride Channels

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Ion Channels and Transporters of Epithelia in Health and Disease

Part of the book series: Physiology in Health and Disease ((PIHD))

Abstract

This article focuses on activators and inhibitors of ClC-2. ClC-2 Cl− channels from mouse, rabbit, rat, and human have been studied extensively in recombinant form by whole-cell patch-clamp and in single-channel studies. There are similarities in responses of these channels from different species to protons, ATP, lipids, and lubiprostone for the recombinant channels. However, there are differences in channel properties, notably in the activation of human and rabbit (but not rat or mouse) forms by PKA. Two PKA phosphorylation sites of human ClC-2 have been identified by mutagenesis. One is required for lipid and lubiprostone activation. Structural studies suggest that these sites interact with cystathionine-β-synthase (CBS) domains to regulate ClC-2. Single-channel studies have been carried out on recombinant ClC-2, cortical astrocytes, and A6 cells which have both ClC-2 and CFTR in the apical membrane. Methadone and GaTx2 differentially inhibit ClC-2, while DASU-02 differentially inhibits CFTR. CFTRinh172 and glibenclamide inhibit both. Knockdown of ion channels combined with pharmacology is more powerful than using pharmacological agents alone. Studies using human cells and tissues such as intestine and lung have used various activators and inhibitors, and these studies are reviewed in detail. This review indicates that it is essential to verify the specificity of all agents experimentally to correctly interpret experimental results. Some studies provide insight into the possible roles of ClC-2 in physiological processes.

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Disclosure

JC and DHM are supported by a research grant from Sucampo AG, Zug, Switzerland. JC, DHM, and RU have financial interests in Sucampo Pharmaceuticals, Inc.

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Authors and Affiliations

  1. Department of Molecular and Cellular Physiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0576, USA

    John Cuppoletti & Danuta H. Malinowska

  2. VLP Therapeutics, 19 Firstfield Road, Suite 100B, Gaithersburg, MD, 20878, USA

    Ryuji Ueno

Authors
  1. John Cuppoletti
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  2. Danuta H. Malinowska
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  3. Ryuji Ueno
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Correspondence to John Cuppoletti .

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Editors and Affiliations

  1. Department of Physiology, University of Otago , Dunedin, Otago, New Zealand

    Kirk L. Hamilton

  2. Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Daniel C Devor

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Cuppoletti, J., Malinowska, D.H., Ueno, R. (2016). ClC-2 Chloride Channels. In: Hamilton, K., Devor, D. (eds) Ion Channels and Transporters of Epithelia in Health and Disease. Physiology in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-3366-2_15

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