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J. Biol. Chem., Vol. 279, Issue 20, 21160-21168, May 14, 2004

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Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator Channel by -Adrenergic Agonists and Vasoactive Intestinal Peptide in Rat Smooth Muscle Cells and Its Role in Vasorelaxation^*

Renaud Robert, Vincent Thoreau, Caroline Norez, Anne Cantereau, Alain Kitzis, Yvette Mettey¶, Christian Rogier, and Frédéric Becq||

From the Laboratoire des Biomembranes et Signalisation Cellulaire CNRS Unité Mixte de Recherche 6558, Université de Poitiers, 86022 Poitiers, France, Laboratoire de Génétique Cellulaire et Moléculaire, Unité Propre de Recherche de l'Enseignement Superieur EA 2622, Centre Hospitalier Universitaire de Poitiers, 86022 Poitiers, France, and ^¶Laboratoire de Chimie Organique, Faculté de Médecine et de Pharmacie de Poitiers, BP 199, 86002 Poitiers Cedex, France

The signaling events that regulate vascular tone include voltage-dependent Ca²⁺ influx and the activities of various ionic channels; which molecular entities are involved and their role are still a matter of debate. Here we show expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl^- channel in rat aortic smooth muscle cells. Immunoprecipitation and in vitro protein kinase A phosphorylation show the appearance of mature band C of CFTR. An immunohistochemistry study shows CFTR proteins in smooth muscles of aortic rings but not in skeletal muscles. Using the iodide efflux method, a combination of agonists and pharmacological agents was used to dissect the function of CFTR. Agonists of the cAMP pathway, the -adrenergic agonist isoproterenol, and the neuropeptide vasoactive intestinal peptide activate CFTR-dependent transport from cells maintained in a high but not low extracellular potassium-rich saline, suggesting that depolarization of smooth muscle is critical to CFTR activation. Smooth muscle CFTR possesses all of the pharmacological attributes of its epithelial homologues: stimulation by the CFTR pharmacological activators MPB-07 (EC₅₀ = 158 µM) and MPB-91 (EC₅₀ = 20 µM) and inhibition by glibenclamide and diphenylamine-2-carboxylic acid but not by 5,11,17,23-tetrasulfonato-25,26,27,28-tetramethoxy-calix[4]arene. Contraction measurements on isolated aortic rings were performed to study the contribution of CFTR to vascular tone. With aortic rings (without endothelium) preconstricted by high K⁺ saline or by the -adrenergic agonist norepinephrine, CFTR activators produced a concentration-dependent relaxation. These results identify for the first time the expression and function of CFTR in smooth muscle where it plays an unexpected but fundamental role in the autonomic and hormonal regulation of the vascular tone.

Received for publication, November 7, 2003 , and in revised form, March 8, 2004.

^* This work is in partial fulfillment of Ph.D. requirements for R. R. and was supported by a fellowship from Vaincre la Mucoviscidose (VLM). This work was also supported by grants from VLM and CNRS. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. E-mail: frederic.becq{at}univ-poitiers.fr.

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