Table 1.
Examples of chloride-channel subtypes, functions and modulators
| Protein | Mechanism of regulation |
Channel properties | Physiological roles | Human diseases | Pharmacological modulators |
|---|---|---|---|---|---|
| CFTR | Activated by cyclic AMP-dependent phosphorylation | Linear I–V; Cl− > I− permeability | Cl− secretion by epithelial cells in airways, submucosal glands, pancreas, intestine and testis; Cl− absorption in sweat glands | Cystic fibrosis | Multiple, nanomolar-potency activators and inhibitors |
| ClC-1 | Activated by depolarization | Cl− > I− permeability; double-barrelled pore | Cl− conductance in skeletal muscle; repolarization after action potential | Myotonia | Weak inhibition by 9-AC, niflumic acid and DPC |
| ClC-2 | Slowly activated by hyperpolarization and cell swelling | Inward rectification of I–V; Cl− > I− permeability | Cl− homeostasis in neurons; cell-volume regulation | Epilepsy (controversial) | Weak inhibition by classical Cl− channel blockers, inhibited by Zn2+ |
| ClC-4 and ClC-5 | None identified | Electrogenic H+/Cl− exchange; strong outward rectification | Intracellular Cl− channels facilitating endosomal and synaptic vesicle acidification | ClC-5: Dent’s disease (proteinuria and kidney stones) | No known inhibitors |
| ClC-7 | Requires OSTM1 for membrane expression | Electrogenic H+/Cl− exchanger | Acidification of resorption lacuna in osteoblasts; lysosomal acidification | Osteopetrosis; lysosomal storage disease | No known inhibitors |
| ClC-Ka and ClC-Kb | Weak voltage-dependence; both require barttin for membrane targeting | Moderate outward rectification of I–V; Cl− > I− permeability | Transepithelial Cl− transport in kidney tubules and inner ear | ClC-Kb: Bartter’s syndrome (deafness when barttin affected) | Inhibited by phenylbenzofuran carboxylic acids |
| Bestrophins | Activated by elevated cytosolic Ca2+ | I− > Cl− permeability | Cl− transport in retinal pigment epithelium; Ca2+-stimulated Cl− secretion in epithelia | Best vitelliform macular dystrophy | Weakly inhibited by niflumic acid and stilbenes |
| TMEM16A (anoctamin-1) | Activated by elevated cytosolic Ca2+ | I− > Cl− permeability | Ca2+-stimulatd Cl− secretion in epithelia; smooth-muscle contraction | Not known | Strongly inhibited by niflumic acid and NPPB |
| GABA receptor | Activated by GABA | I− > Cl− permeability | Inhibitory synaptic transmission in the brain | Epilepsy | Potentiated by benzodiazepines and barbiturates |
| Glycine receptor | Activated by glycine, β-alanine and taurine | I− > Cl− permeability | Inhibitory synaptic transmission in the spinal cord | Hyperekplexia | Inhibited by strychnine and picrotoxin |
9-AC, 9-anthracene-carboxylic acid; CFTR, cystic fibrosis transmembrane conductance regulator; ClC, voltage-gated chloride channel; DPC, diphenylcarboxylate; GABA, γ-aminobutyric acid; I–V, current–voltage relationship; NPPB, 5-nitro-2-(3-phenylpropylamino)benzoic acid; OSTM1, osteopetrosis associated transmembrane protein 1.