Chloride Channels

Abstract

Chloride channels are integral membrane proteins that regulate the movement of chloride ions across cellular membranes. They perform a vital role in physiological processes such as epithelial transport, the regulation of nerve and muscle cell membrane excitability, cell volume regulation and in determining the pH within cytoplasmic membrane‐bound organelles. Several distinct protein families form chloride channels whose opening is regulated by different stimuli including neurotransmitter binding, changes in the concentrations of intracellular second messengers including cAMP and Ca2+, and phosphorylation. High‐resolution protein structures of many types of chloride channels have been solved by x‐ray crystallography and cryo‐electron microscopy. Mutations in genes encoding chloride channels impair their function and cause a variety of genetic diseases. Several clinically useful medicines act by modulating the activity of specific types of chloride channels.

Key Concepts

  • Chloride channels are ion channels that facilitate the movement of chloride ions across cell membranes.
  • Chloride channels play fundamental roles in diverse physiological processes.
  • Several distinct gene families encode proteins that function as chloride channels and have unique atomic structures.
  • Genetic diseases result due to mutations in chloride channels that impair their function.
  • The mechanism of action of a number of drugs used clinically involves chloride channels as specific targets.

Keywords: ion channel; membrane transport; physiology; epithelial transport; neurotransmission; synapse; secretory diarrhoea; skeletal muscle; cystic fibrosis

Figure 1. Direction of net chloride movement in two cells, one with high intracellular chloride (a) and one with low chloride (b). (a) When the intracellular chloride concentration is higher, the electrical force on the chloride ions dominates and chloride ions move out of the cell; (b) When the intracellular chloride concentration is low, the chemical driving force dominates and chloride moves into the cell.
Figure 2. Schematic illustration of a chloride secretory epithelium such as the intestinal crypt cells. Chloride is transported across the basolateral membrane, into the cell, through the ion‐coupled chloride cotransporter (Na+/K+/2Cl cotransporter). This raises the intracellular chloride concentration so that, when the apical membrane chloride channel opens, chloride flows out of the cell into the lumen. This results in vectorial movement of chloride from the blood to the intestinal lumen.
Figure 3. Schematic illustration of the transmembrane topology of CFTR: NBF, nucleotide‐binding fold; R, regulatory domain, the location of multiple phosphorylation sites. NH2 indicates the N‐terminus of the protein, COOH indicates the C‐terminus of the protein.
Figure 4. Structure of human CFTR in the apo‐ATP state in ribbon view. (a) Side view. Dashed lines indicate the approximate position of the plasma membrane; (b) Top view of channel from the extracellular side. Colour scheme in both panels, transmembrane segments 1‐6, teal; NBF‐1, orange; transmembrane segments 7‐12, green; NBF‐2, yellow. The R‐domain was disordered and not seen in the structure. Images generated using Chimera ver. 1.14 software with Protein Database (PDB) file 5auk. Adapted from Liu, F., Zhang, Z., Csanády, L., Gadsby, D. C., & Chen, J. (2017). Molecular Structure of the Human CFTR Ion Channel. Cell, 169(1), 85–95.e8. doi:10.1016/j.cell.2017.02.024.
Figure 5. Structure of the glutamate‐gated chloride channel, a member of the Cys‐loop gene superfamily of neurotransmitter‐gated ion channels. This channel is homologous to the GABAA and glycine receptors. (a) Top view from the extracellular side. The channel is a homopentamer, but each subunit has a separate colour to distinguish the subunits; (b) Top view of the transmembrane channel‐forming domain where the extracellular domain has been removed. The anion conducting pathway runs along the central channel axis and is largely lined by residues from the second transmembrane α‐helix (TM2). The positions of the other three transmembrane α helical segments, TM1, TM3 and TM4 are indicated for the purple subunit; (c) Side view of the channel. ECD, extracellular domain; TMD, transmembrane domain. Dashed blue lines indicate the approximate extent of the plasma membrane. Note that the cytoplasmic domain formed by the large loop between TM3 and TM4 was removed from the construct used to obtain this structure (Hibbs and Gouaux, ). Images generated using Chimera ver. 1.14 software with Protein Database (PDB) file 5auk. Adapted from Hibbs, R. E., & Gouaux, E. (2011). Principles of activation and permeation in an anion‐selective Cys‐loop receptor. Nature, 474(7349), 54–60. doi:10.1038/nature10139.
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Further Reading

Hille B (2001) Ion Channels of Excitable Membranes, 3rd edn. Oxford University Press: Sunderland, MA, USA.

Planells‐Case R and Jentsch TJ (2009) Chloride channelopathies. Biochimica et Biophysica Acta – Molecular Basis of Disease 1792: 173–189.

Zheng J and Trudeau MC (2016) Handbook of Ion Channels, 1st edn. CRC Press: Boca Raton.

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Akabas, Myles H(Jul 2020) Chloride Channels. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000039.pub3]