Activation of G551D CFTR channel with MPB-91: Regulation by ATPase activity and phosphorylation
| Autor: | L. Daniel Howell, Jonathan A. Cohn, Christoph Randak, Yvette Mettey, Caroline Norez, Renaud Dérand, Laurence Bulteau-Pignoux, Michel Joffre, Frédéric Becq, Jean Michel Vierfond, Luis J. V. Galietta, Leila Romio, Olga Zegarra-Moran |
|---|---|
| Přispěvatelé: | Dérand, R, Bulteau-Pignoux, L, Mettey, Y, Zegarra-Moran, O, Howell, L D, Randak, C, Galietta, L J, Cohn, J A, Norez, C, Romio, L, Vierfond, J M, Joffre, M, Becq, F |
| Předmět: |
Adenosine Triphosphatase
congenital hereditary and neonatal diseases and abnormalities Patch-Clamp Techniques Physiology ATPase Chloride Channel Enzyme Activator Patch-Clamp Technique Thyroid Gland Enzyme Activators Cystic Fibrosis Transmembrane Conductance Regulator CHO Cells Cystic fibrosis Chloride Channels Cricetinae Gene expression medicine Animals Phosphorylation Protein kinase A Ion transporter Adenosine Triphosphatases chemistry.chemical_classification Iodide biology Animal Cell Biology Iodides medicine.disease Cystic fibrosis transmembrane conductance regulator Rats Inbred F344 Rats Cell biology Electrophysiology Enzyme chemistry Biochemistry CHO Cell Quinolizine biology.protein Rat Quinolizines |
| Zdroj: | Scopus-Elsevier CIÊNCIAVITAE |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|