CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)
Acid Vesicles

Author: Gianpiero Pescarmona
Date: 01/09/2007

Description

Factors affecting mRNA synthesis

Atrial natriuretic peptide modulates cystic fibrosis transmembrane conductance regulator chloride channel expression in rat proximal colon and human intestinal epithelial cells., 2006

[Functional compartmentation of the endocrine action of cardiac natriuretic peptides], 2000

Thyroid hormones stimulate renal expression of CFTR., 2007

Expression of CFTR in human and bovine thyroid epithelium.,1997

Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes.2007

Flavonoide/Crataegus-Forschungsprojekt CFTR

NF-kappa B mediates up-regulation of CFTR gene expression in Calu-3 cells by interleukin-1beta. 2001

tumor necrosis factor alpha and interferon gamma reduce the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (CFTR) in HT-29 and T84 cells by acting post-transcriptionally. We have investigated the effect of the pro-inflammatory peptide interleukin 1beta (IL-1beta) on the expression of the CFTR in Calu-3 cells. IL-1beta increased the production of CFTR mRNA in a dose- and time-dependent manner. Its action was inhibited by inhibitors of the NF-kappaB pathway, REF 2001

Proinflammatory cytokines inhibit secretion in rat bile duct epithelium.

Factors affecting protein activity

cftr metformin

Vasopressin-stimulated CFTR Cl- currents are increased in the renal collecting duct cells of a mouse model of Liddle's syndrome.

Tissue differential expression

Acinar origin of CFTR-dependent airway submucosal gland fluid secretion., 2007

Functions

Of fertility, cystic fibrosis and the bicarbonate ion 2006

Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. 2001

Changes in ion transport in inflammatory disease. 2006

Yet Another Role for the Cystic Fibrosis Transmembrane Conductance Regulator, 2000

Mechanisms of acid and base secretion by the airway epithelium. 2006

CFTR and cell proliferation

Lysophosphatidic acid inhibits cholera toxin-induced secretory diarrhea through CFTR-dependent protein interactions.

Immune system and cystic fibrosis

Incapacitating the immune system in cystic fibrosis

2007
(Ant:forse cancer maggior freq in Cl- elevato per questo?)

CFTR and cholesterol synthesis

J Cyst Fibros. 2009 Oct 27. [Epub ahead of print]
Prevalence of dyslipidemia in adults with cystic fibrosis.

Rhodes B, Nash EF, Tullis E, Pencharz PB, Brotherwood M, Dupuis A, Stephenson A.

Toronto Adult Cystic Fibrosis Program, St. Michael's Hospital, 30 Bond Street, 6th Floor, Toronto, ON, Canada M5B 1W8.

BACKGROUND: A high fat calorie diet is advocated for patients with cystic fibrosis (CF) however the lipid profiles of individuals with CF, including those with CF-related diabetes (CFRD), are not well studied. METHODS: We conducted a retrospective review of adult CF patients attending St Michael's Hospital between January 2005 and December 2007. RESULTS: 334 patients (77% pancreatic insufficient (PI)) were included in the study. Mean HDL cholesterol was significantly lower in males (p<0.0001) with 44% of males having HDL cholesterol <38.7mg/dL(1mmol/L). Pancreatic sufficient patients were more likely than PI subjects to have total cholesterol >201mg/dL(5.2mmol/L) (p<0.01). 5% of subjects had triglyceride concentrations >195mg/dL(2.2mmol/L). Diabetes was diagnosed in 23% of subjects. Lipid profiles were similar between diabetics and non-diabetics. Total cholesterol and triglycerides both increased with increasing age and increasing BMI (p<0.01). CONCLUSION: Dyslipidemia occurs in CF patients however no differences in lipid profiles were seen between those with diabetes and those without. Fasting lipids should be monitored in CF patients, particularly those with PS, older age, and high BMI. As survival in CF increases, the prevalence of dyslipidemia may increase resulting in clinically important complications.

J Cyst Fibros. 2009 Oct 27. [Epub ahead of print]
Prevalence of dyslipidemia in adults with cystic fibrosis.

Rhodes B, Nash EF, Tullis E, Pencharz PB, Brotherwood M, Dupuis A, Stephenson A.

Toronto Adult Cystic Fibrosis Program, St. Michael's Hospital, 30 Bond Street, 6th Floor, Toronto, ON, Canada M5B 1W8.

BACKGROUND: A high fat calorie diet is advocated for patients with cystic fibrosis (CF) however the lipid profiles of individuals with CF, including those with CF-related diabetes (CFRD), are not well studied. METHODS: We conducted a retrospective review of adult CF patients attending St Michael's Hospital between January 2005 and December 2007. RESULTS: 334 patients (77% pancreatic insufficient (PI)) were included in the study. Mean HDL cholesterol was significantly lower in males (p<0.0001) with 44% of males having HDL cholesterol <38.7mg/dL(1mmol/L). Pancreatic sufficient patients were more likely than PI subjects to have total cholesterol >201mg/dL(5.2mmol/L) (p<0.01). 5% of subjects had triglyceride concentrations >195mg/dL(2.2mmol/L). Diabetes was diagnosed in 23% of subjects. Lipid profiles were similar between diabetics and non-diabetics. Total cholesterol and triglycerides both increased with increasing age and increasing BMI (p<0.01). CONCLUSION: Dyslipidemia occurs in CF patients however no differences in lipid profiles were seen between those with diabetes and those without. Fasting lipids should be monitored in CF patients, particularly those with PS, older age, and high BMI. As survival in CF increases, the prevalence of dyslipidemia may increase resulting in clinically important complications.

Decreased total serum coenzyme-Q10 concentrations: a longitudinal study in children with cystic fibrosis.
J Pediatr. 2008 Sep;153(3):402-7.
Laguna TA, Sontag MK, Osberg I, Wagener JS, Accurso FJ, Sokol RJ.

OBJECTIVE: To assess total serum levels of coenzyme Q(10) (Co-Q(10)), an important antioxidant, in children with cystic fibrosis (CF) and to investigate an association between Co-Q(10) level and clinical outcome. STUDY DESIGN: Co-Q(10) levels were measured annually in a prospective cohort study of 381 children with CF. A total of 1092 serum levels of total Co-Q(10) were obtained by high-performance liquid chromatography and ultraviolet light detection. Associations of Co-Q(10) with demographic variables and clinical outcomes were investigated. RESULTS: Of the 381 initial total serum Co-Q(10) measurements, 188 were in the deficient range. Low Co-Q(10) was significantly more prevalent in patients with pancreatic insufficiency (PI) (55%) compared with patients with pancreatic sufficiency (PS) (3%); 22% of the patients with PI exhibited persistently low Co-Q(10) levels. Low Co-Q(10) levels were significantly associated with Pseudomonas aeruginosa colonization in patients with PI and CF under age 24 months, but not with subsequent lung function or hospitalization rates. Low Co-Q(10) levels were related to other markers of nutritional status, including total lipids, beta-carotene, and alpha-tocopherol. CONCLUSIONS: Persistently low total serum Co-Q(10) levels are common in children with CF and PI. A prospective study is indicated to determine whether Co-Q(10) supplementation in CF is beneficial.

Comments
2009-05-23T22:43:23 - sabrina crivellaro

DEFINITION

The CFTR glycoprotein, essential in the apical membrane of epithelial cell to maintain ion and fluid homeostasis, is unique as it is the only member of the large adenine nucleotide-binding cassette (ABC) protein family known to function as an ion channel.
The absence of this precisely regulated anion channel activity results in the failure of ionic and water homeostasis on exocrine epithelial surfaces .

WikigenesCFTR
OMIM*602421
GeneCardsURL

CHEMICAL STRUCTURE AND IMAGES

Genomic sequence

Transcript sequence

Protein Aminoacids Percentage

SYNTHESIS AND TURNOVER

CFTR : FROM GENE TO PROTEIN

The CFTR gene is located on the long arm of chromosome 7 (7q31), contains 27 exons.
The CFTR gene encodes a 1480-amino acid long transmembrane protein with a symmetrical structure : a repeat composed of a transmembrane region (TMD) containing six transmembrane helices ( TM ) and a nucleotide binding domain (NBD), separated by a large hydrophilic regulatory ( R ) domain. These features are characteristic for ABC transporters, but the R domain, is unique for CFTR.

The CFTR polypeptide is integrated in the endoplasmic reticulum (ER) membrane and is glycosylated through addition of two glycosylation groups on its fourth extracellular loop. In this way, the molecular weight of the CFTR protein increases from 130 to 150 kDa.

With chaperone molecules, like calnexin and Hsp70, the polypeptide is correctly folded, and is transported to the Golgi. In this last compartment, the glycosylation groups are further modified to form a mature protein of 170 kDa. It is this last form that will be transported to the cell membrane of CFTR expressing cells where it can function as a chloride channel.
The mature protein has a half-life of 16 h and is ultimately recruited from the cell membrane to be targeted to the lysosomes for degradation.

The folding process in the ER is apparently very inefficient: only 25% of the produced translation products attain a protease resistant form that allows transport to the Golgi-stacks. The remainder is not able to fold into its protease resistant form and is degraded in an ubiquitin-dependent pathway by proteasome complex. The link between CFTR degradation and maturation is formed by chaperone molecules. Hsc70 interacts specifically with the immature form of CFTR. The degradation of ubiquinated proteins occurs in the cytoplasm. Transport of ubiquinated CFTR from the ER to the cytosol is therefore necessary.
Regulation of CFTR-expression is thus very complex at both the transcriptional level by the initiation of transcription, the position of transcription start sites and the formation of alternatively spliced transcripts, and at the (post)-translational level where the equilibrium between protein maturation and degradation is determined by at least two factors, ubiquination and the action of different chaperones.

CELLULAR FUNCTIONS

THE CFTR PROTEIN FUNCTIONS AS A CHLORIDE CHANNEL

The regulation of the CFTR chloride channel is very complex. Multiple kinases can activate the CFTR chloride channel but only protein kinase A-dependent activation of CFTR has been described in detail. First the R domain is phosphorylated by cAMP-dependent protein kinase A (PKA). This allows binding of ATP to nucleotide binding domain 1. When ATP is hydrolyzed by NBD1, the channel opens and anions can flow, according to the electrochemical gradient, through the pore formed by the transmembrane domains. When the R domain is fully phosphorylated, the second nucleotide-binding domain can bind ATP. This event stabilizes the open state of the chloride channel and results in longer openings. When in a next step ATP is hydrolyzed at NBD2 and ADP and Pi are released from both NBDs, the channel will close again.

CFTR MUTATION

When Cystic Fibrosis Transmembrane Conductance Regulator gene is defective, it is responsible of the Cystic Fibrosis disease (CF).The ΔF508 CFTR mutation is by far the most common mutant allele, accounting for some 70% of all mutant CFTR alleles. This mutation is a deletion of CTT, containing the third nucleotide of the ATC codon for isoleucine at position 507 and the first two TT nucleotides of the TTT codon for phenylalanine at position 508 within the first NBD. The wild-type ATC codon becomes ATT,which also codes for isoleucine, and the normal coding sequence of a GGT codon for glycine at position 509 remains intact. ΔF508 CFTR protein is mostly retained in the endoplasmic reticulum but slowly leaks to the endoplasmic reticulum-Golgi intermediate compartment. The low level of membrane expression of CFTR in ΔF508-homozygous cells result in low or unmeasurable chloride ion conductance.

2008-04-02T04:46:35 - Gianpiero Pescarmona

Papers CFTR Salivary

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