CFTR

Cystic fibrosis, a disease of the Caucasian population, is associated with defective CL regulation and is essentially a disorder of epithehal cells (113,114). The defect arises at several levels in the CL ion transporter, ie, the cystic fibrosis transmembrane regulation (CFTR), and is associated with defective CL transport and defective processing, whereby the protein is not correctiy incorporated into the cell membrane. The most common mutation, affecting approximately 60% of patients, is termed F 608 and designates the loss of phenylalanine at this position. This mutation appears to be at least 50,000 years old, which suggests that its survival may have had evolutionary significance (115). 

The gene defective in cystic fibrosis codes for CFTR (cystic fibrosis transmembrane condnctance regulator), a membrane protein that pumps CP out of cells. If this CP pump is defective, CP ions remain in cells, which then take up water from the surrounding mucus by osmosis. The mucus thickens and accumulates in various organs, including the lungs, where its presence favors infections such as pneumonia. Left untreated, children with cystic fibrosis seldom survive past the age of 5 years. 

CFTR has a single-channel conductance of about 8 pS. It is present in the apical membranes of many epithelia. Its mutation leads to the potentially lethal disease cystic fibrosis. In addition to acting as a chloride channel, CFTR is also thought to regulate, e.g., the epithelial sodium channel ENaC, a molecularly unknown outwardly-rectifying chloride channel, and possibly also potassium channels and water channels. Some of these potential regulatory processes, however, are controversial. CFTR also acts as a receptor for bacteria. 

CFTR is the only member of the very large ABC-transpoiter gene family that is known to function as a... 

The PDE3 inhibitor, cilostazol, has been used as an antithrombotic agent and is currently being used in patients being treated for intermittent claudication. Cilostazol is also used for the prevention of restenosis after treatments such as angioplasty. Another PDE3 selective inhibitor, milrinone, has been used in the treatment of congestive heart failure. Milrinone also has been shown to increase the conductance of the CFTR transporter in vitro. 

Disorders caused by misfolded mutant proteins that fail to pass the quality control system of the ER (e.g., mutations of the cystic fibrosis transmembrane regulator protein (CFTR) causing cystic fibrosis). The mutant proteins are retrotranslocated into the cytosol and finally subjected to proteolysis. In some... 

Cystic fibrosis Cystic fibrosis transmembrane conductance regulator (CFTR) Benzo(c)quinolizinium derivatives, VRT-325... 

Cystic fibrosis (MIM 219700) Mutations in the gene encoding the CFTR protein, a Cl" transporter... 

Figure 41-17. Diagram of the structure of the CFTR protein (not to scale). The protein contains twelve transmembrane segments (probably helical), two nucleotide-binding folds or domains (NBFl and NBF2), and one regulatory (R) domain. NBFl and NBF2 probably bind ATP and couple its hydrolysis to transport of Cl . Phe 508, the major locus of mutations in cystic fibrosis, is located in NBFl.

Cystic fibrosis (MIM 219700) CFTR(C - channel) Lungs, pancreas... 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

The mechanism of action proposed is based on a direct binding to the channel and the following partial block of the ATP-binding pocket of CFTR (French et al., 1997), a mechanism similar to that used by genistein to inhibit the activity of other ATP-utilizing enzymes such as protein kinases and topoisomerase II (Polkowski and Mazurek, 2000 and refs therein). The selection of flavonoid compounds or the development of synthetic drugs reasonably selective for CFTR activation might be an area for future clinical trials. 

FRENCH p J, HUMAN J, HOT A G, BooMARS w E, SCHOLTE B J and D E JONGE H R (1997) Genistein activates CFTR Crchannels via a tyrosine kinase- and protein phosphatase-independent mechanism. dm J Physiol. 273 (2 Ptl) C747-C753. 

ILLEK B, FISCHER H, SANTOS G F, WIDDICOMBE J H, MACHEN T E and REENSTRA W W (1995) cAMP-independent activation of CFTR Cl channels by the tyrosine kinase inhibitor genistein. ./Physiol. 268 (4 Ptl) C886-C893. 

SUAUD L, LI J, JIANG Q, RUBENSTEIN R c and KLEYMAN T R (2002) Genisteiu restores functional interactions between Delta F508-CFTR and EnaC in Xenopus ooc)ites. J Biol Chem. Ill (11) 8928-33. 

WEINREICH F, WOOD p G, RiORDAN J R and N AGEL G (1997) Direct action of genistein on CFTR. Pfluegers Arch. 434 (4) 484-91. 

O In CF, the cystic fibrosis transmembrane regulator (CFTR) chloride channel is dysfunctional and usually results in decreased chloride secretion and increased sodium absorption, leading to altered viscosity of fluid excreted by the exocrine glands and mucosal obstruction. 

Abnormally high concentrations of sodium and chloride are found in sweat due to impaired reabsorption within the sweat duct from loss of CFTR channels. Patients are usually asymptomatic (other than a characteristic salty taste to the skin).2 In rare instances such as hot weather or excessive sweating during physical activity, patients may become dehydrated and experience symptoms of hyponatremia (nausea, headache, lethargy, and confusion). Similar CFTR defects are also seen in the salivary glands, manifested by increased saliva viscosity and impaired salivary function. 

Diagnosis of CF is based on two separate elevated sweat chloride concentrations of greater than or equal to 60 mEq/L (or mmol/L) obtained through pilocarpine iontophoresis (referred to as the sweat test ). Genetic testing (CFTR mutation analysis) may be performed to confirm the diagnosis, screen in utero, or detect carrier status. More than 70% of diagnoses are made by 12 months of age and almost all are made by age 12. 

Significant strides have been made in past decades with development of new therapies that have led to the ever-lengthening CF life-span. Since the discovery of the CF gene and the CFTR protein defect, research has focused on gene therapy as a way to restore normal CFTR function through DNA transfer. 

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