Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Br J Pharmacol
1999 May 01;1272:369-76. doi: 10.1038/sj.bjp.0702562.
Show Gene links
Show Anatomy links
Structural and ionic determinants of 5-nitro-2-(3-phenylprophyl-amino)-benzoic acid block of the CFTR chloride channel.
Walsh KB
,
Long KJ
,
Shen X
.
???displayArticle.abstract???
1. The goals of this study were to identify the structural components required for arylaminobenzoate block of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and to determine the involvement of two positively charged amino acid residues, found within the channel, in drug binding. 2. Wild-type and mutant CFTR chloride channels were expressed in Xenopus oocytes and CFTR currents measured using the two microelectrode voltage clamp. Block of the wild-type CFTR current by 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) occurred in a voltage-dependent manner with preferential inhibition of the inward currents (Kd = 166 microM at -90 mV). 3. Removal of the phenyl ring from the aliphatic chain of NPPB, with the compound 2-butylamino-5-nitrobenzoic acid, caused only a small change in CFTR inhibition (Kd = 243 microM), while addition of an extra phenyl ring at this position (5-nitro-2-(3,3-diphenylpropylamino)-benzoic acid) increased drug potency (Kd = 58 microM). In contrast, removal of the benzoate ring (2-amino-4-phenylbutyric acid) or the 5-nitro group (2-(3-phenylpropylamino)-benzoic acid) of NPPB severely limited drug block of the wild-type channel. 4. NPPB inhibition of CFTR currents in oocytes expressing the mutants K335E and R347E also occurred in a voltage-dependent manner. However, the Kds for NPPB block were increased to 371 and 1573 microM, for the K335E and R347E mutants, respectively. 5. NPPB block of the inward wild-type CFTR current was reduced in the presence of 10 mM of the permeant anion SCN-. 6. These studies present the first step in the development of high affinity probes to the CFTR channel.
Anderson,
Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia.
1992, Pubmed
Anderson,
Chloride channels in the apical membrane of normal and cystic fibrosis airway and intestinal epithelia.
1992,
Pubmed
Anderson,
Generation of cAMP-activated chloride currents by expression of CFTR.
1991,
Pubmed
Anderson,
Demonstration that CFTR is a chloride channel by alteration of its anion selectivity.
1991,
Pubmed
Cheung,
Identification of cystic fibrosis transmembrane conductance regulator channel-lining residues in and flanking the M6 membrane-spanning segment.
1996,
Pubmed
,
Xenbase
Cheung,
Locating the anion-selectivity filter of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel.
1997,
Pubmed
Choi,
The internal quaternary ammonium receptor site of Shaker potassium channels.
1993,
Pubmed
,
Xenbase
Cunningham,
cAMP-stimulated ion currents in Xenopus oocytes expressing CFTR cRNA.
1992,
Pubmed
,
Xenbase
Hipper,
Mutations in the putative pore-forming domain of CFTR do not change anion selectivity of the cAMP activated Cl- conductance.
1995,
Pubmed
,
Xenbase
Kartner,
Expression of the cystic fibrosis gene in non-epithelial invertebrate cells produces a regulated anion conductance.
1991,
Pubmed
Linsdell,
Disulphonic stilbene block of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in a mammalian cell line and its regulation by a critical pore residue.
1996,
Pubmed
Linsdell,
Multi-Ion mechanism for ion permeation and block in the cystic fibrosis transmembrane conductance regulator chloride channel.
1997,
Pubmed
Linsdell,
Flickery block of single CFTR chloride channels by intracellular anions and osmolytes.
1996,
Pubmed
Mansoura,
Cystic fibrosis transmembrane conductance regulator (CFTR) anion binding as a probe of the pore.
1998,
Pubmed
,
Xenbase
McCarty,
Voltage-dependent block of the cystic fibrosis transmembrane conductance regulator Cl- channel by two closely related arylaminobenzoates.
1993,
Pubmed
,
Xenbase
McDonough,
Novel pore-lining residues in CFTR that govern permeation and open-channel block.
1994,
Pubmed
Riordan,
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.
1989,
Pubmed
Riordan,
The cystic fibrosis transmembrane conductance regulator.
1993,
Pubmed
Sheppard,
Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents.
1992,
Pubmed
Sheppard,
Mechanism of glibenclamide inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in a murine cell line.
1997,
Pubmed
Tabcharani,
Halide permeation in wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels.
1997,
Pubmed
Tabcharani,
Multi-ion pore behaviour in the CFTR chloride channel.
1993,
Pubmed
Tilmann,
Different types of blockers of the intermediate-conductance outwardly rectifying chloride channel in epithelia.
1991,
Pubmed
Walsh,
Arylaminobenzoate block of the cardiac cyclic AMP-dependent chloride current.
1998,
Pubmed
Walsh,
Effect of chloride channel blockers on the cardiac CFTR chloride and L-type calcium currents.
1996,
Pubmed
Wangemann,
Cl(-)-channel blockers in the thick ascending limb of the loop of Henle. Structure activity relationship.
1986,
Pubmed
Woodhull,
Ionic blockage of sodium channels in nerve.
1973,
Pubmed