Molecular pharmacology of the CFTR Cl− channel

doi:10.1016/S0165-6147(99)01386-3

Trends in Pharmacological Sciences

Volume 20, Issue 11, 1 November 1999, Pages 448-453

https://doi.org/10.1016/S0165-6147(99)01386-3 Get rights and content

Abstract

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl⁻ channel is associated with a wide spectrum of disease. In the search for modulators of CFTR, pharmacological agents that interact directly with the CFTR Cl⁻ channel have been identified. Some agents stimulate CFTR by interacting with the nucleotide-binding domains that control channel gating, whereas others inhibit CFTR by binding within the channel pore and preventing Cl⁻ permeation. Knowledge of the molecular pharmacology of CFTR might lead to new treatments for diseases caused by the dysfunction of CFTR.

Section snippets

Activators of CFTR

To date, over 800 disease-causing mutations have been identified in the CFTR gene (see http://www.genet.sickkids.on.ca/cftr/). Based on studies of the molecular mechanisms of CFTR Cl⁻ channel dysfunction, Welsh and Smith¹³ proposed a classification of CF-associated mutations. They identified four general mechanisms that disrupt protein production, protein processing, channel regulation and channel conduction. Importantly, many CF-associated mutations have some residual Cl⁻ channel function when

Inhibitors of CFTR

Some diseases, such as polycystic kidney disease and secretory diarrhoea, might involve increased activity of the CFTR Cl⁻ channel8, 9; this suggests that the development of therapeutically active inhibitors of CFTR might prove to be of value in the treatment of disease. A variety of agents with diverse chemical structures inhibit CFTR (Fig. 1b). These agents have several characteristics in common: all are anions, most are lipophilic and many are large in size.

Concluding remarks

A molecular understanding of the pharmacology of the CFTR Cl⁻ channel is beginning to emerge. Researchers have identified activators and inhibitors of CFTR, explored structure–activity relationships and investigated the mechanism of action of CFTR modulators. Nevertheless, knowledge of the molecular pharmacology of CFTR remains superficial and many questions remain to be addressed.

A particularly important question is the identity of the binding sites for activators of CFTR. Although there is

Acknowledgements

We thank our laboratory colleagues for helpful discussions, M. E. Krouse and S. M. Travis for valuable comments, and C. Randak for permission to cite work prior to publication. T-C. H. is supported by the National Institutes of Health, the Cystic Fibrosis Foundation and the American Heart Association, Missouri Affiliate. D. N. S. is supported by the Biotechnology and Biological Sciences Research Council, the Cystic Fibrosis Trust, and the National Kidney Research Fund.

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Trends in Pharmacological Sciences

ReviewMolecular pharmacology of the CFTR Cl− channel

Abstract

Section snippets

Activators of CFTR

Inhibitors of CFTR

Concluding remarks

Acknowledgements

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Neuron

Trends Neurosci.

Biophys. J.

Biophys. J.

Curr. Opin. Neurobiol.

Science

Physiol. Rev.

Physiol. Rev.

Annu. Rev. Physiol.

Physiol. Rev.

Science

Physiol. Rev.

J. Clin. Invest.

J. Clin. Invest.

Science

Proc. Natl. Acad. Sci. U. S. A.

Am. J. Physiol.

Pflügers Arch.

Biochemistry

Br. J. Pharmacol.

Am. J. Physiol.

Am. J. Physiol.

Am. J. Physiol.

Review
Molecular pharmacology of the CFTR Cl⁻ channel