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 GABA(A) (gamma-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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Chloride channels as drug targets

Mammalian cells utilize a wide variety of cell volume regulatory mechanisms. For rapid adjustment of cell volume cells release or accumulate ions through respective channels and transport systems acro

The Diversity of Volume Regulatory Mechanisms

Osmotic regulation of neuronal activity: a new role for taurine and glial cells in a hypothalamic neuroendocrine structure.

Most cells have in their cytosols substantial (i.e., umillimolar) concentrations of low molecular weight organic solutes which, together, make a significant contribution to the total intracellular osmolality and which are known collectively as ‘organic osmolytes’. The solutes fulfilling this role fall, in most cases, into one of three different classes: amino acids (e.g., the a-amino acids alanine and proline, and the b-amino acids taurine and b-alanine), polyols (e.g., sorbitol and myo-inositol), and methylamines (e.g., betaine and glycerophosphoryl choline). Such compounds are either synthesized within the cell or taken up from the extracellular medium via accumulative (‘active’) transport systems. In contrast to inorganic ions which, at high concentrations, destabilize protein structure, these organic solutes exert a stabilizing influence on intracellular proteins and, for this reason, are termed ‘compatible solutes’ (Yancey, 1994). The identity and intracellular concentrations of the major organic osmolytes vary between cell-types, as well as with the conditions to which the cells are exposed. Intracellular levels of these compounds increase markedly in response to cell shrinkage. Conversely, a common phenomenon that has been demonstrated for a wide range of cells is that such compounds are released in response to an acute increase in the cell volume, as occurs, for example, following a sudden decrease in the extracellular osmolality. Their loss from the cell is accompanied by a net efflux of water and this process thereby serves as part of the cell’s volume-regulatory response. From studies of swelling-activated organic osmolyte transport in cells from a diverse range of organisms it has emerged that the transport pathways involved share a number of functional characteristics. There is increasing evidence that these pathways are, in many cases and perhaps in general, channels that have a significant permeability to a wide variety of both charged and uncharged solutes. The purpose of this review is to summarize what is currently known about these pathways in eukaryotic cells. The focus is on the properties of the pathways themselves. The mechanisms underlying their volume-sensitivity and the regulatory processes involved in their activation are not considered in any detail. Current ideas concerning the functional and molecular characteristics of the pathways are discussed. However, before turning to these issues it is relevant to consider the relative contribution that these pathways make to the process of ‘regulatory volume decrease’ (RVD) in different cell and tissue types.

Swelling-activated organic osmolyte channels.

The osmolyte function of amino acids and Cl in native NIH/3T3 cells not expressing the P-glycoprotein was examined by investigating the free amino acid concentration and the swelling-activated effl...

Volume regulation in NIH/3T3 cells not expressing P-glycoprotein. II. Chloride and amino acid fluxes

The effects of the Cl channel blockers 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), 1,9-dideoxyforskolin (DDF), dipyridamole, and niflumic acid and of the polyunsaturated fatty acids arachidonic, linolenic, and linoleic acids on regulatory volume decrease (RVD) and associated 125I and [3H]taurine fluxes in cultured rat cerebellar granule neurons were examined. Dose-response curves of NPPB, DDF, and dipyridamole showed 20-100% inhibition of RVD and osmolyte fluxes. Niflumic acid was less potent, requiring 150-600 microM to show effects of this magnitude. The polyunsaturated fatty acids (5-20 microM) inhibited 80-90% RVD and osmolyte fluxes, with arachidonic acid exhibiting the most potent effect. The volume-associated taurine efflux was somewhat higher in younger neurons, but the pharmacological sensitivity was essentially the same in immature and mature cells. The effects of all tested drugs on 125I and [3H]taurine fluxes were remarkably similar, indicating a close pharmacological sensitivity of the transport mechanism for the two osmolytes. This is in line with the suggestion of a common pathway for the volume-associated release of Cl and amino acids functioning as osmolytes.

Cl channel blockers inhibit the volume-activated efflux of Cl and taurine in cultured neurons

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Cl channel blockers inhibit the volume-activated efflux of Cl and taurine in cultured neurons