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The Cystic Fibrosis Transmembrane Regulator (CFTR) in the kidney
MORALES, MARCELO M.;FALKENSTEIN, DORIS;LOPES, ANíBAL GIL;
Anais da Academia Brasileira de Ciências , 2000, DOI: 10.1590/S0001-37652000000300013
Abstract: the cystic fibrosis transmembrane regulator (cftr) is a cl - channel. mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the cystic fibrosis disease (cf). in spite of the high expression of cftr in the kidney, patients with cf do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. cftr mrna is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (ccd) and medullary (imcd) collecting ducts. several studies have demonstrated that cftr does not only transport cl - but also secretes atp and, thus, controls other conductances such as na+ (enac) and k+ (romk2) channels, especially in ccd. in the polycystic kidney the secretion of chloride through cftr contributes to the cyst enlargement. this review is focused on the role of cftr in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.
The Cystic Fibrosis Transmembrane Regulator (CFTR) in the kidney  [cached]
MORALES MARCELO M.,FALKENSTEIN DORIS,LOPES ANíBAL GIL
Anais da Academia Brasileira de Ciências , 2000,
Abstract: The cystic fibrosis transmembrane regulator (CFTR) is a Cl- channel. Mutations of this transporter lead to a defect of chloride secretion by epithelial cells causing the Cystic Fibrosis disease (CF). In spite of the high expression of CFTR in the kidney, patients with CF do not show major renal dysfunction, but it is known that both the urinary excretion of drugs and the renal capacity to concentrate and dilute urine is deficient. CFTR mRNA is expressed in all nephron segments and its protein is involved with chloride secretion in the distal tubule, and the principal cells of the cortical (CCD) and medullary (IMCD) collecting ducts. Several studies have demonstrated that CFTR does not only transport Cl- but also secretes ATP and, thus, controls other conductances such as Na+ (ENaC) and K+ (ROMK2) channels, especially in CCD. In the polycystic kidney the secretion of chloride through CFTR contributes to the cyst enlargement. This review is focused on the role of CFTR in the kidney and the implications of extracellular volume regulators, such as hormones, on its function and expression.
Lack of correlation between pulmonary disease and cystic fibrosis transmembrane conductance regulator dysfunction in cystic fibrosis: a case report
Hara Levy, Carolynn L Cannon, Daniel Asher, Christopher García, Robert H Cleveland, Gerald B Pier, Michael R Knowles, Andrew A Colin
Journal of Medical Case Reports , 2010, DOI: 10.1186/1752-1947-4-117
Abstract: We describe a pair of African-American brothers, aged 21 and 27, with cystic fibrosis. They were homozygous for a rare frameshift mutation in the cystic fibrosis transmembrane conductance regulator 3791delC, which would be expected to cause significant morbidity. Although 80% of cystic fibrosis patients are colonized with Pseudomonas aeruginosa by eight years of age, the older brother had no serum opsonic antibody titer to P. aeruginosa by age 13 and therefore would have failed to mount an effective antibody response to the alginate (mucoid polysaccharide) capsule of P. aeruginosa. He was not colonized with P. aeruginosa until 24 years of age. Similarly, the younger brother was not colonized with P. aeruginosa until age 20 and had no significant lung disease.Despite a prevailing idea in cystic fibrosis research that the amount of functional cystic fibrosis transmembrane conductance regulator predicts clinical status, our results indicated that respiratory disease severity in cystic fibrosis exhibits phenotypic heterogeneity. If this heterogeneity is, in part, genetic, it is most likely derived from genes outside the cystic fibrosis transmembrane conductance regulator locus.Mutations in both alleles of the cystic fibrosis transmembrane conductance regulator (CFTR) gene result in the disease cystic fibrosis (CF), which manifests classically as chronic sinopulmonary disease, pancreatic insufficiency, elevated sodium chloride loss in sweat, infertility among men is due to agenesis of the vas deferens and other symptoms like liver disease. Except for patients with significant liver disease, the primary disease morbidity is linked to the chronic pulmonary infections and consequent decline in lung function. CFTR mutations are classified as severe (class I-III mutations) or mild (class IV-V mutations) based on their effect on protein synthesis and function, implying that the less CFTR that is made or is functional, the more severe the clinical course of a patient with cysti
Structure and function of the cystic fibrosis transmembrane conductance regulator
Morales, M.M.;Capella, M.A.M.;Lopes, A.G.;
Brazilian Journal of Medical and Biological Research , 1999, DOI: 10.1590/S0100-879X1999000800013
Abstract: cystic fibrosis (cf) is a lethal autosomal recessive genetic disease caused by mutations in the cf transmembrane conductance regulator (cftr). mutations in the cftr gene may result in a defective processing of its protein and alter the function and regulation of this channel. mutations are associated with different symptoms, including pancreatic insufficiency, bile duct obstruction, infertility in males, high sweat cl-, intestinal obstruction, nasal polyp formation, chronic sinusitis, mucus dehydration, and chronic pseudomonas aeruginosa and staphylococcus aureus lung infection, responsible for 90% of the mortality of cf patients. the gene responsible for the cellular defect in cf was cloned in 1989 and its protein product cftr is activated by an increase of intracellular camp. the cftr contains two membrane domains, each with six transmembrane domain segments, two nucleotide-binding domains (nbds), and a cytoplasmic domain. in this review we discuss the studies that have correlated the role of each cftr domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying cl- channels (orccs).
Structure and function of the cystic fibrosis transmembrane conductance regulator  [cached]
Morales M.M.,Capella M.A.M.,Lopes A.G.
Brazilian Journal of Medical and Biological Research , 1999,
Abstract: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). Mutations in the CFTR gene may result in a defective processing of its protein and alter the function and regulation of this channel. Mutations are associated with different symptoms, including pancreatic insufficiency, bile duct obstruction, infertility in males, high sweat Cl-, intestinal obstruction, nasal polyp formation, chronic sinusitis, mucus dehydration, and chronic Pseudomonas aeruginosa and Staphylococcus aureus lung infection, responsible for 90% of the mortality of CF patients. The gene responsible for the cellular defect in CF was cloned in 1989 and its protein product CFTR is activated by an increase of intracellular cAMP. The CFTR contains two membrane domains, each with six transmembrane domain segments, two nucleotide-binding domains (NBDs), and a cytoplasmic domain. In this review we discuss the studies that have correlated the role of each CFTR domain in the protein function as a chloride channel and as a regulator of the outwardly rectifying Cl- channels (ORCCs).
Functional Interactions of HCO3- with Cystic Fibrosis Transmembrane Conductance Regulator  [cached]
Gray MA,O'Reilly C,Winpenny J,Argent BE
JOP Journal of the Pancreas , 2001,
Abstract: Disruption of normal cystic fibrosis transmembrane conductance regulator- (CFTR)-mediated Cl(-) transport is associated with cystic fibrosis (CF). CFTR is also required for HCO(3)(-) transport in many tissues such as the lungs, gastro-intestinal tract, and pancreas, although the exact role CFTR plays is uncertain. Given the importance of CFTR in HCO(3)(-) transport by so many CF-affected organ systems, it is perhaps surprising that relatively little is known about the interactions of HCO(3)(-) ions with CFTR. We have used patch clamp recordings from native pancreatic duct cells to study HCO(3)(-) permeation and interaction with CFTR. Ion selectivity studies shows that CFTR is between 3-5 times more selective for Cl(-) over HCO(3)(-). In addition, extracellular HCO(3)(-) has a novel inhibitory effect on cAMP-stimulated CFTR currents carried by Cl(-). The block by HCO(3)(-) was rapid, relatively independent of voltage and occurred over the physiological range of HCO(3)(-) concentrations. These data show that luminal HCO(3)(-) acts as a potent regulator of CFTR, and suggests that inhibition involves an external anion-binding site on the channel. This work has implications not only for elucidating mechanisms of HCO(3)(-) transport in epithelia, but also for approaches used to treat CF.
Human Amnion Epithelial Cells Induced to Express Functional Cystic Fibrosis Transmembrane Conductance Regulator  [PDF]
Sean V. Murphy, Rebecca Lim, Philip Heraud, Marian Cholewa, Mark Le Gros, Martin D. de Jonge, Daryl L. Howard, David Paterson, Courtney McDonald, Anthony Atala, Graham Jenkin, Euan M. Wallace
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046533
Abstract: Cystic fibrosis, an autosomal recessive disorder caused by a mutation in a gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), remains a leading cause of childhood respiratory morbidity and mortality. The respiratory consequences of cystic fibrosis include the generation of thick, tenacious mucus that impairs lung clearance, predisposing the individual to repeated and persistent infections, progressive lung damage and shortened lifespan. Currently there is no cure for cystic fibrosis. With this in mind, we investigated the ability of human amnion epithelial cells (hAECs) to express functional CFTR. We found that hAECs formed 3-dimensional structures and expressed the CFTR gene and protein after culture in Small Airway Growth Medium (SAGM). We also observed a polarized CFTR distribution on the membrane of hAECs cultured in SAGM, similar to that observed in polarized airway cells in vivo. Further, hAECs induced to express CFTR possessed functional iodide/chloride (I?/Cl?) ion channels that were inhibited by the CFTR-inhibitor CFTR-172, indicating the presence of functional CFTR ion channels. These data suggest that hAECs may be a promising source for the development of a cellular therapy for cystic fibrosis.
Cl--Dependent HCO3- Transport by Cystic Fibrosis Transmembrane Conductance Regulator
Choi JY,Lee MG,Ko S,Muallem S
JOP Journal of the Pancreas , 2001,
Abstract: Cystic fibrosis (CF) affects the function of multiple organs. The inability to maintain luminal hydration of ducts leads to their plugging and destruction of the affected organs. An exacerbating problem is the acidic pH of the fluid produced by CF patients' secretory glands. This is best documented for pancreatic secretion. Alkaline fluid secretion requires vectorial transport of electrolytes and of HCO(3)(-). The mechanism of HCO(3)(-) secretion by cystic fibrosis transmembrane conductance regulator (CFTR) expressing cells is not well understood. In the present communication we discuss results suggesting that CFTR itself can transport large amounts of HCO(3)(-) and that HCO(3)(-) transport by CFTR is mediated by a coupled, Cl(-)-dependent process that is different from a simple HCO(3)(-) conductance.
Cystic Fibrosis Transmembrane Conductance Regulator and H+ Permeability in Regulation of Golgi pH  [cached]
Machen TE,Chandy G,Wu M,Grabe M
JOP Journal of the Pancreas , 2001,
Abstract: This paper reviews experiments from this lab that have tested the hypothesis that pH of the Golgi (pH(G)) of cystic fibrosis (CF) airway epithelial cells is alkaline compared to normal, that this altered pH affects sialyltransferase and other Golgi enzymes controlling biochemical composition of the plasma membrane and that altered surface biochemistry increases bacterial binding. We generated a plasmid encoding a modified green fluorescence protein-sialyltransferase (GFP-ST) chimera protein that was pH-sensitive and localized to the Golgi when transfected into HeLa cells and also CF and normal or cystic fibrosis transmembrane conductance regulator- (CFTR)-corrected airway epithelial cells. Digital imaging microscopy of these Golgi-localized probes showed that there was no correlation between pH(G) (6.4-7.0) and the presence of CFTR, whether cells were in HCO(3)(-)/CO(2)-containing or in HCO(3)(-)/CO(2)-free solutions. Activation of CFTR by raising cell [cAMP] had no effect on pH(G). Thus, CFTR seemed not to be involved in controlling pH(G). Experiments on HeLa cells using an avidin-sialyltransferase chimera in combination with a pH-sensitive fluorescent biotin indicated that even in cells that do not express CFTR, Cl(-) and K(+) conductances of the Golgi and other organelle membranes were large and that pH(G) was controlled solely by the H(+) v-ATPase countered by a H(+) leak. A mathematical model was applied to these and other published data to calculate passive H(+) permeability (P(H+)) of the Golgi, endoplasmic reticulum, trans-Golgi network, recycling endosomes and secrety granules from a variety of cells. An organelle's acidity was inversely correlated to its calculated P(H+). We conclude that the CFTR plays a minor role in organelle pH regulation because other (Cl(-) and K(+)) channels are present in sufficient numbers to shunt voltages generated during H(+) pumping. Acidity of the Golgi (and perhaps other organelles) appears to be determined by the activity of H(+) pumps countered by H(+) leaks.
Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis  [cached]
Nico Derichs
European Respiratory Review , 2013,
Abstract: Cystic fibrosis (CF) is caused by genetic mutations that affect the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These mutations can impact the synthesis and transfer of the CFTR protein to the apical membrane of epithelial cells, as well as influencing the gating or conductance of chloride and bicarbonate ions through the channel. CFTR dysfunction results in ionic imbalance of epithelial secretions in several organ systems, such as the pancreas, gastrointestinal tract, liver and the respiratory system. Since discovery of the CFTR gene in 1989, research has focussed on targeting the underlying genetic defect to identify a disease-modifying treatment for CF. Investigated management strategies have included gene therapy and the development of small molecules that target CFTR mutations, known as CFTR modulators. CFTR modulators are typically identified by high-throughput screening assays, followed by preclinical validation using cell culture systems. Recently, one such modulator, the CFTR potentiator ivacaftor, was approved as an oral therapy for CF patients with the G551D-CFTR mutation. The clinical development of ivacaftor not only represents a breakthrough in CF care but also serves as a noteworthy example of personalised medicine.
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