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ORIGINAL ARTICLE

Transfected 3- but Not 2-Adrenergic Receptors Regulate Cystic Fibrosis Transmembrane Conductance Regulator Activity via a New Pathway Involving the Mitogen-Activated Protein Kinases Extracellular Signal-Regulated Kinases

Institut du Thorax, Institut National de la Sante et de la Recherche Medicale U533, Faculté de Médecine, Nantes, France (A.R., G.T., C.G.); Laboratoire de Pharmacologie de la Faculté de Pharmacie, Institut National de la Sante et de la Recherche Medicale EMI-0356, Université Victor Segalen Bordeaux 2, Bordeaux, France (V.L.); and Faculté des Sciences et Techniques, Nantes, France (C.G.)

Abstract

We have shown previously that in a heterologous mammalian expression system A549 cells, ₃-adrenoceptor (₃-AR) stimulation regulates the activity of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The present investigation was carried out to determine the signaling pathway involved in this regulation. A549 cells were intranuclearly injected with plasmids encoding human CFTR and ₃-AR. CFTR activity was functionally assessed by microcytofluorimetry. The application of 1 µM 4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2-1 hydrochloride (CGP-12177), a ₃-AR agonist, produced a CFTR activation that was not abolished by protein kinase A inhibitors. In pertussis toxin-pretreated cells, the CFTR activation induced by CGP-12177 was abolished. The overexpression of -adrenoceptor receptor kinase, an inhibitor of subunits, abolished the CGP-12177–induced CFTR activation, suggesting the involvement of subunits of G_i/o proteins. The pretreatment of A549 cells with selective inhibitors of either phosphoinositide 3-kinase (PI3K), wortmannin, and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinase (MAPK), 2'-amino-3'-methoxyflavone (PD98059), and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), abolished the effects of CGP-12177 on the CFTR activity. Immunohistochemical assays showed that only the cells expressing ₃-AR exhibited MAPK activation in response to CGP-12177. Furthermore, CFTR activity increased in cells pretreated with 10% fetal bovine serum both in A549 cells injected only with CFTR and in T84 cells, which endogenously express CFTR, indicating that CFTR activity can be regulated by the MAPK independently of the ₃-AR stimulation. In conclusion, we have demonstrated that CFTR is regulated through a G_i/o/PI3K/ERK1/2 MAPK signaling cascade dependently or not on an activation of ₃-ARs. This pathway represents a new regulation for CFTR.

Address correspondence to: Dr. Chantal Gauthier, Institut du Thorax, Inserm U533, Faculté de Médecine, 1 rue Gaston Veil, BP 53508, F-44035 Nantes, France. E-mail: chantal.gauthier{at}nantes.inserm.fr

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