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Chloride Channelopathies of ClC-2
Miao Miao Bi 1,2,, Sen Hong 3,, Hong Yan Zhou 2, Hong Wei Wang 4, Li Na Wang 2 and Ya Juan Zheng 1,*
Department of Ophthalmology, the China-Japan Union Hospital, Jilin University, Changchun 130033, Jilin, China; E-Mails: (H.Y.Z.); (L.N.W.)
These authors contributed equally to this work.
Received: 26 September 2013; in revised form: 14 November 2013 / Accepted: 16 December 2013 /
Published: 27 December 2013


ClCs; ClC-2; ClC-2 channels; ClC-2 chloride channelopathies

1. Introduction




2. Biophysical Properties of ClC-2






3. Pharmacological Properties of ClLC-2


3.1. ClC-2 Inhibitors



3.2. ClC-2 Activators



4. Molecular Features of ClC-2

4.1. Basic Protein Structure


4.2. Structure-Function Relationships




4.3. Promoter Region



5. Cellular Function of ClC-2


5.1. Regulation of Cell Volume


5.2. Regulation of Transepithelial Transport


5.3. Regulation of Tight Junction Function


5.4. Regulation of Pacemaker Activity



5.5. Regulation of Vascular Smooth Muscle Cell (VSMC) Proliferation


5.6. Regulation of Glioma Cell Proliferation


5.7. Regulation of Neuronal Excitability


5.8. Important Notes to Consider


6. Regulation of ClC-2 Expression and Function


6.1. Expression Regulation

6.1.1. Transcriptional Regulation





6.1.2. Transcript Stabilization


6.1.3. Ubiquitination


6.1.4. Trafficking Regulation



6.1.5. Regulation by Hormones Thyroid Hormone




6.1.6. Alpha1-Adrenoceptors


6.1.7. Dynein Motor Complex


6.2. Functional Regulation


6.2.1. Acidification


6.2.2. Protein Kinase A (PKA)





6.2.3. Epidermal Growth Factor Receptor (EGFR)


6.2.4. Arachidonic Acid and Amidation


6.2.5. Heat-Shock Proteins


6.2.6. Actin Cytoskeleton


6.2.7. Intracellular ATP


6.2.8. Membrane Cholesterol Content


7. ClC-2 Channelopathies


7.1. Eye Disease

7.1.1. Retinal Degeneration



7.1.2. Sjögren’s Syndrome


7.2. Male Infertility

7.2.1. Testicular Degeneration


7.2.2. Azoospermia


7.3. Chronic Constipation and Irritable Bowel Syndrome


7.4. Neuronal Disease

7.4.1. Epilepsy






7.4.2. Leukoencephalopathy



7.5. Cystic Fibrosis Disease



7.6. Cardiovascular Disease


8. Conclusions and Perspectives






Conflicts of Interest

The authors declare no conflict of interest.


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Figure 2. Molecular/structural features of ClC-2 channels. The predicted membrane topology of a ClC-2 monomer is shown.

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Figure 3. ClC-2 chloride channelopathies. Schematic illustration of human diseases that can be caused by loss of ClC-2 channels.

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