Journal article
Activation of G551D CFTR channel with MPB-91: regulation by ATPase activity and phosphorylation
American Journal of Physiology: Cell Physiology, Vol.281(5), pp.C1657-C1666
11/01/2001
DOI: 10.1152/ajpcell.2001.281.5.C1657
PMID: 11600430
Abstract
We have designed and synthesized benzo[c]quinolizinium derivatives and evaluated their effects on the activity of G551D cystic fibrosis transmembrane conductance regulator (CFTR) expressed in Chinese hamster ovary and Fisher rat thyroid cells. We demonstrated, using iodide efflux, whole cell patch clamp, and short-circuit recordings, that 5-butyl-6-hydroxy-10-chlorobenzo[c]quinolizinium chloride (MPB-91) restored the activity of G551D CFTR (EC50 = 85 μM) and activated CFTR in Calu-3 cells (EC50 = 47 μM). MPB-91 has no effect on the ATPase activity of wild-type and G551D NBD1/R/GST fusion proteins or on the ATPase, GTPase, and adenylate kinase activities of purified NBD2. The activation of CFTR by MPB-91 is independent of phosphorylation because 1) kinase inhibitors have no effect and 2) the compound still activated CFTR having 10 mutated protein kinase A sites (10SA-CFTR). The new pharmacological agent MPB-91 may be an important candidate drug to ameliorate the ion transport defect associated with CF and to point out a new pathway to modulate CFTR activity.
Details
- Title: Subtitle
- Activation of G551D CFTR channel with MPB-91: regulation by ATPase activity and phosphorylation
- Creators
- Renaud Dérand - Laboratoire de Physiologie des Régulations Cellulaires, Unité Mixte de Recherche 6558, 86022 Poitiers, andLaurence Bulteau-Pignoux - Laboratoire de Physiologie des Régulations Cellulaires, Unité Mixte de Recherche 6558, 86022 Poitiers, andYvette Mettey - Laboratoire de Chimie Organique, Faculté de Médecine et de Pharmacie, 86005 Poitiers, FranceOlga Zegarra-Moran - Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genoa 16148, ItalyL. Daniel Howell - Durham Veterans Affairs and Duke University Medical Center, Durham, North Carolina; andChristoph Randak - Kinderklinik im Dr. von Haunerschen Kinderspital, Ludwig-Maximilians-Universität, Munich, GermanyLuis J. V Galietta - Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genoa 16148, ItalyJonathan A Cohn - Durham Veterans Affairs and Duke University Medical Center, Durham, North Carolina; andCaroline Norez - Laboratoire de Physiologie des Régulations Cellulaires, Unité Mixte de Recherche 6558, 86022 Poitiers, andLeila Romio - Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genoa 16148, ItalyJean-Michel Vierfond - Laboratoire de Chimie Organique, Faculté de Médecine et de Pharmacie, 86005 Poitiers, FranceMichel Joffre - Laboratoire de Physiologie des Régulations Cellulaires, Unité Mixte de Recherche 6558, 86022 Poitiers, andFrédéric Becq - Laboratoire de Physiologie des Régulations Cellulaires, Unité Mixte de Recherche 6558, 86022 Poitiers, and
- Resource Type
- Journal article
- Publication Details
- American Journal of Physiology: Cell Physiology, Vol.281(5), pp.C1657-C1666
- DOI
- 10.1152/ajpcell.2001.281.5.C1657
- PMID
- 11600430
- ISSN
- 0363-6143
- eISSN
- 1522-1563
- Language
- English
- Date published
- 11/01/2001
- Academic Unit
- Pulmonary Medicine; Stead Family Department of Pediatrics
- Record Identifier
- 9984093602702771
Metrics
26 Record Views