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Am J Physiol Cell Physiol
2012 Jan 01;3021:C67-76. doi: 10.1152/ajpcell.00225.2011.
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Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101.
Stahl M, Stahl K, Brubacher MB, Forrest JN.
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Comparison of diverse orthologs is a powerful tool to study the structure and function of channel proteins. We investigated the response of human, killifish, pig, and shark cystic fibrosis transmembrane conductance regulator (CFTR) to specific inhibitors of the channel: CFTR(inh)-172, glibenclamide, and GlyH-101. In three systems, including organ perfusion of the shark rectal gland, primary cultures of shark rectal gland tubules, and expression studies of each ortholog in cRNA microinjected Xenopus laevis oocytes, we observed fundamental differences in the sensitivity to inhibition by these channel blockers. In organ perfusion studies, shark CFTR was insensitive to inhibition by CFTR(inh)-172. This insensitivity was also seen in short-circuit current experiments with cultured rectal gland tubular epithelial cells (maximum inhibition 4 ± 1.3%). In oocyte expression studies, shark CFTR was again insensitive to CFTR(inh)-172 (maximum inhibition 10.3 ± 2.5% at 25 μM), pig CFTR was insensitive to glibenclamide (maximum inhibition 18.4 ± 4.4% at 250 μM), and all orthologs were sensitive to GlyH-101. The amino acid residues considered responsible by previous site-directed mutagenesis for binding of the three inhibitors are conserved in the four CFTR isoforms studied. These experiments demonstrate a profound difference in the sensitivity of different orthologs of CFTR proteins to inhibition by CFTR blockers that cannot be explained by mutagenesis of single amino acids. We believe that the potency of the inhibitors CFTR(inh)-172, glibenclamide, and GlyH-101 on the CFTR chloride channel protein is likely dictated by the local environment and the three-dimensional structure of additional residues that form the vestibules, the chloride pore, and regulatory regions of the channel.
Akabas,
Cystic fibrosis transmembrane conductance regulator. Structure and function of an epithelial chloride channel.
2000, Pubmed
Akabas,
Cystic fibrosis transmembrane conductance regulator. Structure and function of an epithelial chloride channel.
2000,
Pubmed Aller,
Cloning, characterization, and functional expression of a CNP receptor regulating CFTR in the shark rectal gland.
1999,
Pubmed
,
Xenbase Bertrand,
SLC26A9 is a constitutively active, CFTR-regulated anion conductance in human bronchial epithelia.
2009,
Pubmed Bessadok,
Recognition of sulfonylurea receptor (ABCC8/9) ligands by the multidrug resistance transporter P-glycoprotein (ABCB1): functional similarities based on common structural features between two multispecific ABC proteins.
2011,
Pubmed Bewley,
Shark rectal gland vasoactive intestinal peptide receptor: cloning, functional expression, and regulation of CFTR chloride channels.
2006,
Pubmed
,
Xenbase Buchwald,
The search for the cystic fibrosis gene.
1989,
Pubmed Butterworth,
Acute ENaC stimulation by cAMP in a kidney cell line is mediated by exocytic insertion from a recycling channel pool.
2005,
Pubmed Caci,
Evidence for direct CFTR inhibition by CFTR(inh)-172 based on Arg347 mutagenesis.
2008,
Pubmed Cai,
Inhibition of heterologously expressed cystic fibrosis transmembrane conductance regulator Cl- channels by non-sulphonylurea hypoglycaemic agents.
1999,
Pubmed Caputo,
TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity.
2008,
Pubmed Cotten,
Cystic fibrosis-associated mutations at arginine 347 alter the pore architecture of CFTR. Evidence for disruption of a salt bridge.
1999,
Pubmed Dawson,
CFTR: mechanism of anion conduction.
1999,
Pubmed Dean,
The human ATP-binding cassette (ABC) transporter superfamily.
2001,
Pubmed Ge,
Direct comparison of the functional roles played by different transmembrane regions in the cystic fibrosis transmembrane conductance regulator chloride channel pore.
2004,
Pubmed Gong,
Maximization of the rate of chloride conduction in the CFTR channel pore by ion-ion interactions.
2004,
Pubmed Gong,
Mechanism of lonidamine inhibition of the CFTR chloride channel.
2002,
Pubmed Gong,
Mutation-induced blocker permeability and multiion block of the CFTR chloride channel pore.
2003,
Pubmed Gong,
Coupled movement of permeant and blocking ions in the CFTR chloride channel pore.
2003,
Pubmed Gong,
Molecular determinants and role of an anion binding site in the external mouth of the CFTR chloride channel pore.
2003,
Pubmed Green,
Surface charges and ion channel function.
1991,
Pubmed Gupta,
Point mutations in the pore region directly or indirectly affect glibenclamide block of the CFTR chloride channel.
2002,
Pubmed Hwang,
Molecular pharmacology of the CFTR Cl- channel.
1999,
Pubmed Kelly,
Cystic fibrosis transmembrane regulator inhibitors CFTR(inh)-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition.
2010,
Pubmed Kidd,
Molecular basis for the chloride channel activity of cystic fibrosis transmembrane conductance regulator and the consequences of disease-causing mutations.
2004,
Pubmed Kogan,
Perturbation of the pore of the cystic fibrosis transmembrane conductance regulator (CFTR) inhibits its atpase activity.
2001,
Pubmed Kopeikin,
On the mechanism of CFTR inhibition by a thiazolidinone derivative.
2010,
Pubmed Lehrich,
Vasoactive intestinal peptide, forskolin, and genistein increase apical CFTR trafficking in the rectal gland of the spiny dogfish, Squalus acanthias. Acute regulation of CFTR trafficking in an intact epithelium.
1998,
Pubmed
,
Xenbase Linsdell,
Relationship between anion binding and anion permeability revealed by mutagenesis within the cystic fibrosis transmembrane conductance regulator chloride channel pore.
2001,
Pubmed Linsdell,
Location of a common inhibitor binding site in the cytoplasmic vestibule of the cystic fibrosis transmembrane conductance regulator chloride channel pore.
2005,
Pubmed Liu,
Bioelectric properties of chloride channels in human, pig, ferret, and mouse airway epithelia.
2007,
Pubmed Ma,
Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion.
2002,
Pubmed Mansoura,
Cystic fibrosis transmembrane conductance regulator (CFTR) anion binding as a probe of the pore.
1998,
Pubmed
,
Xenbase Marshall,
Low-conductance anion channel activated by cAMP in teleost Cl- -secreting cells.
1995,
Pubmed Marshall,
Identification and localization of a dogfish homolog of human cystic fibrosis transmembrane conductance regulator.
1991,
Pubmed McCarty,
Permeation through the CFTR chloride channel.
2000,
Pubmed McDonough,
Novel pore-lining residues in CFTR that govern permeation and open-channel block.
1994,
Pubmed Moorhouse,
Single channel analysis of conductance and rectification in cation-selective, mutant glycine receptor channels.
2002,
Pubmed Muanprasat,
Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy.
2004,
Pubmed Ostedgaard,
Processing and function of CFTR-DeltaF508 are species-dependent.
2007,
Pubmed Pilewski,
Role of CFTR in airway disease.
1999,
Pubmed Price,
Function of Xenopus cystic fibrosis transmembrane conductance regulator (CFTR) Cl channels and use of human-Xenopus chimeras to investigate the pore properties of CFTR.
1996,
Pubmed
,
Xenbase Ratner,
Mercury toxicity in the shark (Squalus acanthias) rectal gland: apical CFTR chloride channels are inhibited by mercuric chloride.
2006,
Pubmed
,
Xenbase Riordan,
Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA.
1989,
Pubmed Rosenberg,
Purification and crystallization of the cystic fibrosis transmembrane conductance regulator (CFTR).
2004,
Pubmed Schultz,
Pharmacology of CFTR chloride channel activity.
1999,
Pubmed Schultz,
Glibenclamide blockade of CFTR chloride channels.
1996,
Pubmed Sheppard,
CFTR channel pharmacology: novel pore blockers identified by high-throughput screening.
2004,
Pubmed Sheppard,
Mechanism of glibenclamide inhibition of cystic fibrosis transmembrane conductance regulator Cl- channels expressed in a murine cell line.
1997,
Pubmed Sheppard,
Structure and function of the CFTR chloride channel.
1999,
Pubmed Sheppard,
CFTR channel pharmacology: insight from a flock of clones. Focus on "Divergent CFTR orthologs respond differently to the channel inhibitors CFTRinh-172, glibenclamide, and GlyH-101".
2012,
Pubmed Singer,
A divergent CFTR homologue: highly regulated salt transport in the euryhaline teleost F. heteroclitus.
1998,
Pubmed
,
Xenbase Smith,
Cystic fibrosis transmembrane conductance regulator. Physical basis for lyotropic anion selectivity patterns.
1999,
Pubmed
,
Xenbase Smith,
CFTR: covalent and noncovalent modification suggests a role for fixed charges in anion conduction.
2001,
Pubmed
,
Xenbase St Aubin,
Identification of a second blocker binding site at the cytoplasmic mouth of the cystic fibrosis transmembrane conductance regulator chloride channel pore.
2007,
Pubmed Stewart,
SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization.
2011,
Pubmed
,
Xenbase Tabcharani,
Multi-ion pore behaviour in the CFTR chloride channel.
1993,
Pubmed Thiagarajah,
Prevention of toxin-induced intestinal ion and fluid secretion by a small-molecule CFTR inhibitor.
2004,
Pubmed Thiagarajah,
A small molecule CFTR inhibitor produces cystic fibrosis-like submucosal gland fluid secretions in normal airways.
2004,
Pubmed Valentich,
Cl- secretion by cultured shark rectal gland cells. I. Transepithelial transport.
1991,
Pubmed Vergani,
CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains.
2005,
Pubmed Wang,
Effects of a new cystic fibrosis transmembrane conductance regulator inhibitor on Cl- conductance in human sweat ducts.
2004,
Pubmed Weber,
Mercury and zinc differentially inhibit shark and human CFTR orthologues: involvement of shark cysteine 102.
2006,
Pubmed
,
Xenbase Yamazaki,
Inhibitory effects of glibenclamide on cystic fibrosis transmembrane regulator, swelling-activated, and Ca(2+)-activated Cl- channels in mammalian cardiac myocytes.
1997,
Pubmed Zhang,
Steady-state interactions of glibenclamide with CFTR: evidence for multiple sites in the pore.
2004,
Pubmed
,
Xenbase Zhang,
Architecture of the cystic fibrosis transmembrane conductance regulator protein and structural changes associated with phosphorylation and nucleotide binding.
2009,
Pubmed Zhang,
Time-dependent interactions of glibenclamide with CFTR: kinetically complex block of macroscopic currents.
2004,
Pubmed
,
Xenbase Zhou,
Identification of positive charges situated at the outer mouth of the CFTR chloride channel pore.
2008,
Pubmed Zhou,
Probing an open CFTR pore with organic anion blockers.
2002,
Pubmed
