There are five main classes of chloride channels: cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated, voltage-dependent, ligand-gated and volume-sensitive. Chloride channels are attractive targets for drug development for a wide range of human disorders.
Fluorescence and electrophysiological high-throughput assays are now available for the discovery of chloride-channel modulators. Cell-based assays utilizing halide-sensing yellow fluorescent proteins are particularly useful for rapid, cost-effective screening.
Mutations in CFTR chloride channels cause the hereditary disease cystic fibrosis, and overactivation of CFTR causes secretory diarrhoeas. Small-molecule inhibitors of normal CFTR are in development, as are potentiators and correctors of cystic fibrosis-causing mutant CFTRs.
Calcium-activated chloride channels are involved in a wide range of physiological functions, including transepithelial fluid secretion, oocyte fertilization, olfactory and sensory signal transduction, smooth-muscle contraction, and neuronal and cardiac excitation. Recent advances have been made in the molecular identification of these channels and in the identification of channel activators and inhibitors.
Chloride channels activated by GABA (γ-aminobutyric acid) and glycine (ionotropic receptors) modulate important physiological functions in the central and peripheral nervous system. The large diversity of ionotropic GABA and glycine receptors provide an opportunity to develop drugs to treat various neurological disorders.
Volume-sensitive chloride channels remain to be identified at the molecular level. These channels may be important pharmacological targets in treating cancer and degenerative disorders.
Chloride channels represent a relatively under-explored target class for drug discovery as elucidation of their identity and physiological roles has lagged behind that of many other drug targets. Chloride channels are involved in a wide range of biological functions, including epithelial fluid secretion, cell-volume regulation, neuroexcitation, smooth-muscle contraction and acidification of intracellular organelles. Mutations in several chloride channels cause human diseases, including cystic fibrosis, macular degeneration, myotonia, kidney stones, renal salt wasting and hyperekplexia. Chloride-channel modulators have potential applications in the treatment of some of these disorders, as well as in secretory diarrhoeas, polycystic kidney disease, osteoporosis and hypertension. Modulators of GABAA (γ-aminobutyric acid A) receptor chloride channels are in clinical use and several small-molecule chloride-channel modulators are in preclinical development and clinical trials. Here, we discuss the broad opportunities that remain in chloride-channel-based drug discovery.
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Autosomal dominant polycystic kidney disease
Cystic Fibrosis Foundation Patient Registry Annual Data Report 2006
QualityImprovement/PatientRegistryReport/FDA list of orphan designations and approvals
- Cystic fibrosis
One of the most prevalent life-shortening genetic diseases among Caucasians, characterized by recurrent lung infections, sterility and intestinal malabsorption.
- Meconium ileus
Often one of the early symptoms of cystic fibrosis consisting of intestinal obstruction by thickened meconium (fetal stool).
- Inwardly rectifying
The intrinsic ability of an ion channel to allow higher ion flux at negative (inwardly rectifying) or positive (outwardly rectifying) membrane potentials, even in the presence of a symmetrical concentration of the permeant ion.
The network of polysaccharides present on the surface of many cell types.
- Intestinal loop model
A surgical technique to study fluid absorption/secretion in an isolated intestinal loop of a laboratory animal.
- Airway surface liquid
The layer of fluid (thickness 7–10 μm) covering the airways that allows efficient beating of cilia for mucociliary clearance.
Penetration of more than one spermatozoon into an oocyte at the time of fertilization.
- Best vitelliform macular dystrophy
Early onset degeneration of the macula in retina causing loss of vision.
- Electrical organ
A specialized muscle-derived structure of fish belonging to the genus Torpedo that is able to produce electrical discharges of up to 220 volts.
- Shunt conductance
A pathway that allows flow of ions (often chloride) in parallel with another pathway for ions of opposite charge.
A genetic disease caused by osteoclast loss of function with unbalanced bone growth leading to dense but brittle bones.
The potassium-rich fluid contained in the membranous labyrinth of the inner ear.
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Verkman, A., Galietta, L. Chloride channels as drug targets. Nat Rev Drug Discov 8, 153–171 (2009). https://doi.org/10.1038/nrd2780
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