Cystic fibrosis transmembrane conductance regulator , activation

Biwersi J, Emans N, Verkman AS. Cystic fibrosis transmembrane conductance regulator activation stimulates endosome fusion in vivo. Proc Natl Acad Sci USA 1996 93 12484. 

A novel class of activators for chloride conductance in the cystic fibrosis transmembrane conductance regulator protein has been identified. These 3-(2-benzy-loxyphenyl)isoxazoles and 3-(2-benzyloxyphenyl)isoxazolines have been synthesized employing the 1,3-dipolar cycloaddition of nitrile oxides with various alkene and alkyne dipolarophiles (490). 

Wagner, J. A., T. V. McDonald, P. T. Nghiem, A. W. Lowe, H. Schulman, D. C. Gruenert, L. Stryer, and P. Gardner. 1992. Antisense oligodeoxynucleotides to the cystic fibrosis transmembrane conductance regulator inhibit cAMP-activated but not calcium-activated chloride currents. Proc Natl Acad Sci USA 89(15) 6785-9. 

Extensive studies have been performed on the influence of flavonoids on the properties of the cystic fibrosis transmembrane conductance regulator (CFTR) channel. The best-known CFTR channel activator is genistein (42) [293,294], but this channel could also be activated by apigenin (23), kaempferol (28), and quercetin (29) [295], which appeared to be even more potent activators than genistein (42). CFTR channel activation by genistein (42) was not accompanied by an increase of intracellular cAMP level, which... 

A further type of PM-located GC is gastrointestinal (GI) C-type GC that is activated by the paracrine peptide hormone guanylin. Guanylin is secreted by GI cells and resultant GC activation and cGMP elevation results in increased Cl transport via the cystic fibrosis transmembrane conductance regulator (CFTR) into the intestinal lumen with resultant increased water flow. The Escherkhia coli heat-stable enterotoxin mimics guanylin in activating this intestinal C-type GC and consequently causes diarrhoea. 

L. J. V. Galietta, A. S. Verkman, High-affinity activators of cystic fibrosis transmembrane conductance regulator (CFTR) chloride conductance identified by high-throughput screening, /. Biol. Chem. 2002, 277, 37235-37241. 

Solid-phase Zincke reaction was applied for the search of activators of the cystic fibrosis transmembrane conductance regulator protein. On the other hand, the tripeptide TRH (pGlu-His-Pro-NH2) was shown to be a hypothalamic releasing factor for the regulation of pituitary function. A solid-phase Zincke reaction was used to prepare analogues of TRH having the central histidine replaced with a 1,4-dihydropyridine unit (such as 48). Compound 48 was expected to cross the hydrophobic blood-brain barrier (BBB) but to be trapped within the central nervous system upon oxidation to the hydrophilic pyridinium form. 

Sheppard, D. N. Gai, Z. Activation of the cystic fibrosis transmembrane conductance regulator chloride channel. PCT Int. Appl. WO 2002005793, 2002 Chem. Abstr. 2002,136, 112661. 

Wei L, Vankeerberghen A, Cuppens H, Eggermont J, Cassiman JJ, Droogmans G, NiliusB. Interaction between calcium-activated chloride channels and the cystic fibrosis transmembrane conductance regulator. Pflugers Arch 1999 438 635-641. 

Cationic liposomes complexed with plasmid DNA encoding for cystic fibrosis transmembrane conductance regulator (CFTR) have been administered to nasal epithelium and to airways of patients with mild cystic fibrosis (76,95-97). However, only low levels of gene expression or activity were detected. Moreover, administration of the vectors provoked local and systemic inflammatory responses in several patients (76,96). It is not known whether the inflammatory environment in the CF airways degraded or inactivated the liposomal vectors. 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

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