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Am J Physiol Cell Physiol 281: C1657-C1666, 2001;
0363-6143/01 $5.00
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Vol. 281, Issue 5, C1657-C1666, November 2001

Activation of G551D CFTR channel with MPB-91: regulation by ATPase activity and phosphorylation

Renaud Dérand1, Laurence Bulteau-Pignoux1, Yvette Mettey2, Olga Zegarra-Moran3, L. Daniel Howell4, Christoph Randak5, Luis J. V. Galietta3, Jonathan A. Cohn4, Caroline Norez1, Leila Romio3, Jean-Michel Vierfond2, Michel Joffre1, and Frédéric Becq1

1 Laboratoire de Physiologie des Régulations Cellulaires, Unité Mixte de Recherche 6558, 86022 Poitiers, and 2 Laboratoire de Chimie Organique, Faculté de Médecine et de Pharmacie, 86005 Poitiers, France; 3 Laboratorio di Genetica Molecolare, Istituto G. Gaslini, Genoa 16148, Italy; 4 Durham Veterans Affairs and Duke University Medical Center, Durham, North Carolina; and 5 Kinderklinik im Dr. von Haunerschen Kinderspital, Ludwig-Maximilians-Universität, Munich, Germany

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.

pharmacology; disease-causing mutation; cystic fibrosis; nucleotide binding domains; cystic fibrosis transmembrane conductance regulator


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