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J Biol Chem, Vol. 274, Issue 39, 27415-27425, September 24, 1999
From the a Laboratoire de neurobiologie UPR-9024 CNRS, 31 ch. J. Aiguier F-13402 Marseille cedex 20, France, e Laboratoire
de chimie organique, Faculté de médecine et de pharmacie de
Poitiers, 34 rue du jardin des plantes, 86005, Poitiers, France,
f Department of Physiological Sciences, University Medical
School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United
Kingdom, g Laboratorio di genetica molecolare, Istituto Giannina
Gaslini, 16148 Genova, Italy, h Department of Medical
Biochemistry, University of Wales College of Medicine, Heath Park,
Cardiff, CF4 4XN, United Kingdom, i GRGE, Faculté de
médecine, 27 bld. Jean Moulin, 13385 Marseille, France,
j Laboratoire de biologie cellulaire, Faculté de
médecine et de pharmacie de Poitiers, 34 rue du jardin des
plantes, 86005, Poitiers, France, and b Laboratoire de
physiologie des régulations cellulaires, UMR 6558, Université de Poitiers, 40 avenue du recteur Pineau,
86022 Poitiers, France
Chloride channels play an important role in the
physiology and pathophysiology of epithelia, but their pharmacology is
still poorly developed. We have chemically synthesized a series of
substituted benzo[c]quinolizinium (MPB) compounds. Among them,
6-hydroxy-7-chlorobenzo[c]quinolizinium (MPB-27) and
6-hydroxy-10-chlorobenzo[c]quinolizinium (MPB-07), which we show to
be potent and selective activators of the cystic fibrosis transmembrane
conductance regulator (CFTR) chloride channel. We examined the effect
of MPB compounds on the activity of CFTR channels in a variety of
established epithelial and nonepithelial cell systems. Using the iodide
efflux technique, we show that MPB compounds activate CFTR chloride
channels in Chinese hamster ovary (CHO) cells stably expressing CFTR
but not in CHO cells lacking CFTR. Single and whole cell patch clamp
recordings from CHO cells confirm that CFTR is the only channel
activated by the drugs. Ussing chamber experiments reveal that the
apical addition of MPB to human nasal epithelial cells produces a large
increase of the short circuit current. This current can be totally
inhibited by glibenclamide. Whole cell experiments performed on native
respiratory cells isolated from wild type and CF null mice also show
that MPB compounds specifically activate CFTR channels. The activation of CFTR by MPB compounds was glibenclamide-sensitive and
4,4'-diisothiocyanostilbene-2,2'-disulfonic acid-insensitive. In the
human tracheal gland cell line MM39, MPB drugs activate CFTR channels
and stimulate the secretion of the antibacterial secretory
leukoproteinase inhibitor. In submandibular acinar cells, MPB compounds
slightly stimulate CFTR-mediated submandibular mucin secretion without
changing intracellular cAMP and ATP levels. Similarly, in CHO cells MPB
compounds have no effect on the intracellular levels of cAMP and ATP or
on the activity of various protein phosphatases (PP1, PP2A, PP2C, or
alkaline phosphatase). Our results provide evidence that substituted
benzo[c]quinolizinium compounds are a novel family of activators of
CFTR and of CFTR-mediated protein secretion and therefore represent a
new tool to study CFTR-mediated chloride and secretory functions in
epithelial tissues.
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