scholarly journals Additional Disruption of the ClC-2 Cl-Channel Does Not Exacerbate the Cystic Fibrosis Phenotype of Cystic Fibrosis Transmembrane Conductance Regulator Mouse Models

2004 ◽  
Vol 279 (21) ◽  
pp. 22276-22283 ◽  
Author(s):  
Anselm A. Zdebik ◽  
John E. Cuffe ◽  
Marko Bertog ◽  
Christoph Korbmacher ◽  
Thomas J. Jentsch
Keyword(s):  
Cystic Fibrosis ◽  
Mouse Models ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Cl Channel ◽  
Cystic Fibrosis Transmembrane

scholarly journals Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents.

1992 ◽  
Vol 100 (4) ◽  
pp. 573-591 ◽  
Author(s):  
D N Sheppard ◽  
M J Welsh
Keyword(s):  
Cystic Fibrosis ◽  
Voltage Dependence ◽  
K Channel ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
K Channels ◽  
Intracellular Atp ◽  
Cl Channel ◽  
Cl Channels ◽  
Cystic Fibrosis Transmembrane

The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that is regulated by cAMP-dependent phosphorylation and by intracellular ATP. Intracellular ATP also regulates a class of K+ channels that have a distinct pharmacology: they are inhibited by sulfonylureas and activated by a novel class of drugs called K+ channel openers. In search of modulators of CFTR Cl- channels, we examined the effect of sulfonylureas and K+ channel openers on CFTR Cl- currents in cells expressing recombinant CFTR. The sulfonylureas, tolbutamide and glibenclamide, inhibited whole-cell CFTR Cl- currents at half-maximal concentrations of approximately 150 and 20 microM, respectively. Inhibition by both agents showed little voltage dependence and developed slowly; > 90% inhibition occurred 3 min after adding 1 mM tolbutamide or 100 microM glibenclamide. The effect of tolbutamide was reversible, while that of glibenclamide was not. In contrast to their activating effect on K+ channels, the K+ channel openers, diazoxide, BRL 38227, and minoxidil sulfate inhibited CFTR Cl- currents. Half-maximal inhibition was observed at approximately 250 microM diazoxide, 50 microM BRL 38227, and 40 microM minoxidil sulfate. The rank order of potency for inhibition of CFTR Cl- currents was: glibenclamide < BRL 38227 approximately equal to minoxidil sulfate > tolbutamide > diazoxide. Site-directed mutations of CFTR in the first membrane-spanning domain and second nucleotide-binding domain did not affect glibenclamide inhibition of CFTR Cl- currents. However, when part of the R domain was deleted, glibenclamide inhibition showed significant voltage dependence. These agents, especially glibenclamide, which was the most potent, may be of value in identifying CFTR Cl- channels. They or related analogues might also prove to be of value in treating diseases such as diarrhea, which may involve increased activity of the CFTR Cl- channel.

CFTR mediates electrogenic chloride secretion in mouse inner medullary collecting duct (mIMCD-K2) cells

1995 ◽  
Vol 269 (3) ◽  
pp. C683-C689 ◽  
Author(s):  
D. Vandorpe ◽  
N. Kizer ◽  
F. Ciampollilo ◽  
B. Moyer ◽  
K. Karlson ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Patch Clamp ◽  
Collecting Duct ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Inner Medullary Collecting Duct ◽  
Cl Channel ◽  
Cl Channels ◽  
Medullary Collecting Duct ◽  
Cystic Fibrosis Transmembrane

Previously we demonstrated that the inner medullary collecting duct cell line mIMCD-K2 secretes Cl- by an electrogenic mechanism [N. L. Kizer, B. Lewis, and B. A. Stanton. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F347-F355, 1995; N. L. Kizer, D. Vandorpe, B. Lewis, B. Bunting, J. Russell, and B. A. Stanton. Am. J. Physiol. 268 (Renal Fluid Electrolyte Physiol. 37): F854-F861, 1995]. The goal of the present study was to characterize the Cl- channel responsible for adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated Cl- secretion. To this end, using the patch-clamp technique, we measured Cl- currents. In whole cell patch-clamp experiments, 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (CPT-cAMP) activated Cl- currents that were time and voltage independent, inhibited by diphenylamine 2-carboxylate (DPC), and had a linear current-voltage (I-V) relation. In cell-attached patches of the apical membrane, we identified 7-pS Cl- channels that were stimulated by CPT-cAMP. In inside-out patches with Cl- in the pipette and bath solutions, Cl- currents had a linear I-V relation. The halide permeability sequence was PCl = PBr > PI. The Cl- channel inhibitors DPC, 5-nitro-2-(3-phenylpropylamino)-benzoic acid, and glibenclamide blocked the 7-pS Cl- channel, whereas 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid was ineffective. By reverse transcriptase polymerase chain reaction, we isolated a partial cDNA clone encoding the cystic fibrosis transmembrane conductance regulator in mIMCD-K2 cells. We conclude that cAMP stimulates electrogenic Cl- secretion in inner medullary collecting duct cells by activating cystic fibrosis transmembrane conductance regulator Cl- channels.

scholarly journals Animal Models of Cystic Fibrosis Pathology: Phenotypic Parallels and Divergences

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Gillian M. Lavelle ◽  
Michelle M. White ◽  
Niall Browne ◽  
Noel G. McElvaney ◽  
Emer P. Reeves
Keyword(s):  
Cystic Fibrosis ◽  
Animal Models ◽  
Mouse Models ◽  
Animal Studies ◽  
Mucociliary Clearance ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Bacterial Colonisation ◽  
Transport Defect ◽  
Cystic Fibrosis Transmembrane

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The resultant characteristic ion transport defect results in decreased mucociliary clearance, bacterial colonisation, and chronic neutrophil-dominated inflammation. Much knowledge surrounding the pathophysiology of the disease has been gained through the generation of animal models, despite inherent limitations in each. The failure of certain mouse models to recapitulate the phenotypic manifestations of human disease has initiated the generation of larger animals in which to study CF, including the pig and the ferret. This review will summarise the basic phenotypes of three animal models and describe the contributions of such animal studies to our current understanding of CF.

Sign in / Sign up

Export Citation Format

Share Document