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

Renaud Dérand, Laurence Bulteau-Pignoux, Yvette Mettey, Olga Zegarra-Moran, L. Daniel Howell, Christoph Randak, Luis J V Galietta, Jonathan A. Cohn, Caroline Norez, Leila Romio, Jean Michel Vierfond, Michel Joffre, Frédéric Becq

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalAmerican Journal of Physiology - Cell Physiology
Volume281
Issue number5 50-5
Publication statusPublished - 2001

Keywords

  • Cystic fibrosis
  • Cystic fibrosis transmembrane conductance regulator
  • Disease-causing mutation
  • Nucleotide binding domains
  • Pharmacology

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology
  • Physiology (medical)

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