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Received for publication May 26, 2004.
Revised November 23, 2004.
Accepted for publication November 23, 2004.
We have previously shown 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 CGP 12177, a 3-AR agonist, produced a CFTR activation which was not abolished by protein kinase A inhibitors. In PTX-pretreated cells, the CFTR activation induced by CGP 12177 was abolished. The overexpression of -ARK, an inhibitor of 
subunits, abolished the CGP 12177-induced CFTR activation, suggesting the involvement of subunits of Gi/o proteins. The pretreatment of A549 cells with selective inhibitors of either PI3K, wortmannin and LY 294002, or ERK 1/2 MAPK, PD 98059 and 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 Gi/o-PI3K- ERK 1/2 MAPK signaling cascade dependently or not of an activation of 3-ARs. This pathway represents a new regulation for CFTR.
Key words:
Adrenergic, Ion channel regulation, Gi family, MAP Kinase
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