Mutations in the epithelial Na+ channel ENaC outer pore disrupt amiloride block by increasing its dissociation rate.

Détails

ID Serval
serval:BIB_9FF30DF0E028
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Mutations in the epithelial Na+ channel ENaC outer pore disrupt amiloride block by increasing its dissociation rate.
Périodique
Molecular Pharmacology
Auteur(s)
Kellenberger S., Gautschi I., Schild L.
ISSN
0026-895X[print], 0026-895X[linking]
Statut éditorial
Publié
Date de publication
2003
Volume
64
Numéro
4
Pages
848-856
Langue
anglais
Résumé
The epithelial Na+ channel ENaC mediates transepithelial Na+ transport in the distal kidney, the colon, and the lung and is a key element for the maintenance of Na+ balance and the regulation of blood pressure. Mutagenesis studies have identified residues alphaS583 and the homologous betaG525 and gammaG537 in the outer pore entrance that are critical for ENaC block by the K+-sparing diuretic amiloride. The aim of the present study was to determine first, whether these residues are part of the amiloride binding site, and second, whether they are general determinants of ENaC block by amiloride and its derivatives. Kinetic analysis of the association and dissociation rates of amiloride and benzamil to ENaC showed that mutation of residue alphaS583C and the homologous betaG525C increased the dissociation rate of the drugs from the binding site, with little changes in their association rate. Thus, these mutations destabilize the binding interaction between the blockers and the receptor on the channel, favoring the unbinding of the ligand. This strongly suggests that they are part of the binding site. Because mutations of alphaS583, betaG525, and gammaG537 have similar effects on amiloride, benzamil, and triamterene block, we conclude that these three ENaC blockers share a common receptor within the ion channel pore.
Mots-clé
Amiloride/analogs & derivatives, Amiloride/pharmacology, Animals, Electrophysiology, Epithelial Sodium Channel, Kinetics, Mutagenesis, Site-Directed, Oocytes/drug effects, Oocytes/metabolism, Sodium Channel Blockers/pharmacology, Sodium Channels/drug effects, Sodium Channels/genetics, Transfection, Xenopus laevis
Pubmed
Web of science
Création de la notice
24/01/2008 13:45
Dernière modification de la notice
20/08/2019 16:06
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