Chloride Channels


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 cell volume regulation, epithelial transport, the regulation of nerve and muscle cell membrane excitability and in determining the pH within cytoplasmic membraneā€bound organelles. Several genetic diseases are caused by mutations within chloride channel genes.

Keywords: ion; epithelial transport; membrane excitability; synaptic transmission; 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 the bacterial homologue of the ClC channel. (a) Schematic illustrating the transmembrane topology. α helices shown as cylinders. Note that several of the α helices do not traverse the entire membrane but form reentrant loops. Protein regions participating in forming the ion binding site are in red. Red sphere represents a chloride ion. The protein is formed as an inverted tandem repeat, the N‐terminal half is green and the C‐terminal half is blue. (b) Illustration of the three‐dimensional ClC channel protein structure. Colour scheme as in (a). (c) Top view of the homodimer that contains two of the subunits shown in (b), one in red and the other in blue. α helices are shown as coils. Chloride ions are shown as green balls. Reproduced with permission from Dutzler et al..

Figure 5.

Barttin is an auxiliary β subunit for the kidney ClC‐Ka and ClC‐Kb channels. (a) Illustrates the proposed transmembrane topology of barttin. (b) Illustrates the polarized location of transporters and channels in the Cl absorptive epithelium of the thick ascending limb of the loop of Henle. Note the location of barttin and the ClC‐Kb channels in the basolateral membrane. (c) Illustrates the location of channels and transporters in the K+ secretory epithelium of the inner ear. Note the location of barttin and the ClC channels in the basolateral membrane. (b, c) Reproduced with permission from Estevez et al..

Figure 6.

Overview of GABAA receptor structure. (a) Illustration of top view of channel showing five subunits assembled around central channel axis. The channel is surrounded by an inner ring formed by the five M2 membrane‐spanning segments (blue). The outer helix ring (red) is formed by the M1, M3 and M4 helices from each subunit. (b) GABA or glycine receptor subunit transmembrane topology. (c) 4 Å resolution structure of the homologous acetylcholine receptor. Extracellular domain is shown in green. Membrane‐spanning segments are coloured as in (a). Limits of membrane indicated by black dashed lines. (a, c) Reproduced with permission from Miyazawa et al..



D'Anglemont de Tassigny A, Souktani R, Ghaleh B, Henry P and Berdeaux A (2003) Structure and pharmacology of swelling‐sensitive chloride channels, I(Cl, swell). Fundamental and Clinical Pharmacology 17: 539–553.

Dutzler R, Campbell EB, Cadene M, Chait BT and MacKinnon R (2002) X‐ray structure of a ClC chloride channel at 3.0 Å reveals the molecular basis of anion selectivity. Nature 415: 287–294.

Estevez R, Boettger T and Stein V (2001) Barttin is a Cl− channel β‐subunit crucial for renal Cl− reabsorption and inner ear K+ secretion. Nature 414: 558–561.

Field M (2003) Intestinal ion transport and the pathophysiology of diarrhea. Journal of Clinical Investigation 111: 931–943.

Furst J, Jakab M and Konig M (2000) Structure and function of the ion channel ICln. Cell Physiology and Biochemistry 10: 329–334.

Gadsby DC and Nairn AC (1999) Control of CFTR channel gating by phosphorylation and nucleotide hydrolysis. Physiological Reviews 79: S77–S107.

Gunther W, Piwon N and Jentsch TJ (2003) The ClC‐5 chloride channel knock‐out mouse – an animal model for Dent's disease. Pflugers Archives 445: 456–462.

Jentsch TJ, Steinmeyer K and Schwarz G (1990) Primary structure of Torpedomarmorata chloride channel isolated by expression cloning in Xenopus oocytes. Nature 348: 510–514.

Locher KP, Lee AT and Rees DC (2002) The E. coli BtuCD structure: a framework for ABC transporter architecture and mechanism. Science 296: 1091–1098.

Miyazawa A, Fujiyoshi Y and Unwin N (2003) Structure and gating mechanism of the acetylcholine receptor pore. Nature 423: 949–955.

Moss SJ and Smart TG (2001) Constructing inhibitory synapses. Nature Reviews Neuroscience 2: 240–250.

Paul SM and Beitel GJ (2003) Developmental biology Tubulogenesis CLICs into place. Science 302: 2077–2078.

Qu Z, Weu RW, Mann W and Hartzell HC (2003) Two bestrophins cloned from Xenopus laevis oocytes express Ca2+‐activated Cl− currents. Journal of Biological Chemistry 278: 49563–49572.

Schofield PR (2002) The role of glycine and glycine receptors in myoclonus and startle syndromes. Advances in Neurology 89: 263–274.

Stobrawa SM, Breiderhoff T and Takamori S (2001) Disruption of ClC‐3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29: 185–196.

Tulk BM, Kapadia S and Edwards JC (2002) CLIC1 inserts from the aqueous phase into phospholipid membranes, where it functions as an anion channel. American Journal of Physiology Cell Physiology 282: C1103–C1112.

Xu M and Akabas MH (1996) Identification of channel‐lining residues in the M2 membrane‐spanning segment of the GABA(A) receptor alpha1 subunit. Journal of General Physiology 107: 195–205.

Further Reading

Akabas MH (2000) Cystic fibrosis transmembrane conductance regulator: structure and function of an epithelial chloride channel. Journal of Biological Chemistry 275: 3729–3732.

Akabas MH (2004) GABAA receptor structure–function studies: a reexamination in light of new acetylcholine receptor structures. International Review in Neurobiology 62: 1–43.

Al‐Awqati Q (1995) Chloride channel of intracellular organelles. Current Opinion in Cell Biology 7: 504–508.

Dawson DC, Smith SS and Mansoura MK (1999) CFTR: mechanism of anion conduction. Physiological Reviews 79: S47–S75.

George AL Jr (1998) Chloride channels and endocytosis: ClC‐5 makes a dent. Proceedings of the National Academy of Sciences of the USA 95: 7843–7845.

Hevers W and Luddens H (1998) The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes. Molecular Neurobiology 18: 35–86.

Hille B (2001) Ionic Channels of Excitable Membranes, 3rd edn Sunderland, MA: Sinauer Associates.

Jentsch TJ, Stein V, Weinreich F and Zdebik AA (2002) Molecular structure and physiological function of chloride channels. Physiological Reviews 82: 503–568.

Nilius B and Droogmans G (2003) Amazing chloride channels: an overview. Acta Physiologica Scandinavica 177: 119–147.

Steinmeyer K and Jentsch TJ (1998) Molecular physiology of renal chloride channels. Current Opinion in Nephrology and Hypertension 7: 497–502.

Strange K, Emma F and Jackson PS (1996) Cellular and molecular physiology of volume‐sensitive anion channels. American Journal of Physiology 270: C711–C730.

Szewczyk A (1998) The intracellular potassium and chloride channels: properties, pharmacology and function. Molecular Membrane Biology 15: 49–58.

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Akabas, Myles H(Sep 2005) Chloride Channels. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0004061]