title: Activation of G551D CFTR channel with MPB-91: regulation by ATPase activity and phosphorylation.
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 (EC(50) = 85 microM) and activated CFTR in Calu-3 cells (EC(50) = 47 microM). 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.
authors.affiliation: Laboratoire de Physiologie des Régulations Cellulaires, Unité Mixte de Recherche 6558, 86022 Poitiers, France.
authors.forename: R
authors.initials: R
authors.lastname: Dérand
authors.forename: L
authors.initials: L
authors.lastname: Bulteau-Pignoux
authors.forename: Y
authors.initials: Y
authors.lastname: Mettey
authors.forename: O
authors.initials: O
authors.lastname: Zegarra-Moran
authors.forename: L D
authors.initials: LD
authors.lastname: Howell
authors.forename: C
authors.initials: C
authors.lastname: Randak
authors.forename: L J
authors.initials: LJ
authors.lastname: Galietta
authors.forename: J A
authors.initials: JA
authors.lastname: Cohn
authors.forename: C
authors.initials: C
authors.lastname: Norez
authors.forename: L
authors.initials: L
authors.lastname: Romio
authors.forename: J M
authors.initials: JM
authors.lastname: Vierfond
authors.forename: M
authors.initials: M
authors.lastname: Joffre
authors.forename: F
authors.initials: F
authors.lastname: Becq
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D016466:CHO Cells; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004594:Electrophysiology; D020536:Enzyme Activators / Q000494:pharmacology*; D007454:Iodides / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011807:Quinolizines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C439425:5-butyl-6-hydroxy-10-chlorobenzo(c)quinolizinium chloride; D018118:Chloride Channels; D020536:Enzyme Activators; D007454:Iodides; D011807:Quinolizines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000251:Adenosine Triphosphatases