Ion channels have signalling functions in generating second messengers or functioning as effectors by responding to such messengers. Ion channels are also important effectors in that they mediate the action of different intracellular signalling pathways.
There is a large family of ATP-binding cassette (ABC) transporters, some of which have a signalling role in extruding signalling components from the cell. One of the ABC transporters is the cystic fibrosis transmembrane conductance regulator (CFTR). The CFTR is a transmembrane channel located in epithelial cells that conducts anions (Cl' and HCO3') and contributes to the osmotic gradient for the parallel flow of water in the transporting epithelia. A genetic disease known as cystic fibrosis (CF) has been traced to mutations in this channel (Berridge). When both CFTR genes are defective, there will be no functioning CFTR protein, causing the symptoms of CF (Derichs, 2013). A mutation within the CFTR gene can cause defects in a number of areas such as synthesis, trafficking, stability, function, and regulation of the ion channel (Cheung and Deber, 2008). Over the years, a greater understanding of the CFTR and CF as a whole has led to many promising treatments and possible cures available today which will be discussed later in this review.
Background on Cystic Fibrosis disease and its Complications
Cystic Fibrosis (CF) was earlier referred to as 'mucoviscidosis'. It is a disease marked by an ineffective chloride channel. It was first diagnosed in the 1700s by tasting salty sweat when parents kissed their child on the forehead (Littlewood, 2002). The increased chloride (Cl-) ion concentration of sweat is still the main diagnosis of CF. It was discovered that cystic fibrosis was an autosomal recessive genetic disease. The most common mutation in the CFTR gene that is located at 7q21-34, on the long arm of chromosome 7 associated with cystic fibrosis is ??F508 (Welsh, et al., 2001). CF principally affects the respiratory and digestive systems in young children but the sweat glands and the reproductive system may also be involved (Noone and Knowles, 2001). With the advancement of molecular tools and discovery of the gene responsible for the disease, commercial screening panels can be used as diagnostic tests along with the sweat test to detect CF (Rosenstein and Cutting, 1998). Prenatal screens can be performed and carrier testing is usually recommended for individuals who have a family member diagnosed with CF.
Sweat cools the body while mucus lubricates the respiratory, digestive, and reproductive systems; preventing them from drying out and becoming infected. Within a healthy lung, the mucus is mostly composed of mucin glycoproteins that are secreted onto the membrane of the cell. Mucus is a viscoelastic material that forms a protective covering on the apical surfaces of the respiratory, gastrointestinal, and reproductive epithelial tracts and is a mixture of components secreted apically (luminally) by epithelial and glandular cells in the mucosal epithelium (Rose 2006). Mucin glycoproteins or mucins are major macromolecular components of lung mucus (Kesimer et al. 2008). Mucins (MUCs) are heavily O-glycosylated and the genes that encode their protein part are now identified as the MUC genes. Two of the most important mucins, MUC5AC and MUC5B, appear to be greatly reduced in CF patients (Kreda et al, 2012) and since mucins bind bacteria and aid in clearing
bacteria from the airway, the mucin deficit may increase exposure of the CF epithelium to bacteria or their products and thereby trigger inflammation (Ratjen,2009). The mucus lining of the CF lung is thickened and viscous causing persistent cough and wheezing which is the most common symptom of CF patients. The reduced vitality of the lungs leads to pneumonia and chronic infections by Staphylococcus aureus and Pseudomonas aeruginosa. Bacteria multiply on and interact with the airway cells, which are unable to facilitate the natural killing of these invaders (Knowles and Boucher, 2002). The viscous mucus within the lungs can also be due to an increase in anionic polyelectrolytes, including DNA made from the invading bacteria and DNA released from lysed inflammatory cells (Rose, 2013).
As similar to lungs, patients with CF have a coating of thick mucus within their intestines. Defective CFTR proteins within the digestive system causes impaired intestinal fluid secretion because the water moves into cells filled with chloride that cannot escape. This in turn leads to constipation and mucus filled stool. The thick mucus in the digestive tract can also block pancreatic secretion of digestive enzymes that aid in the digestion and absorption of food. A blocked pancreas in CF patients can lead to pancreas insufficiency, malabsorption of fats and proteins, and a possible deficiency in fat-soluble vitamins (Mousa and Woodley, 2012).
Infertility is another complication in CF adults. Approximately 98% of CF males are infertile and almost all CF males are azoospermic (i.e. no measurable amount of sperm within their semen). Male CF patients typically have congenital bilateral absence of the vans deferens (CBAVD). The body and tail of the epididymides are deformed or absent. The testes may or may not be reduced in size, and the seminal vesicles typically contain various abnormalities (Quekett, 2007). Female CF patients on the other hand do not have any reproductive system abnormalities but may have a hard time getting pregnant due to the blockage of the cervix by mucus (Noone and Knowles, 2001).
CF is common genetic disorder among Caucasian people with incidence of one out of every 3,200 Caucasian births and one out of every 15,000 African-American births. Therefor this gene mutation varies according to the geographical background. The life expectancy of CF patients has increased over the past 40 years. Today it is 35 years (In 2005 it was 36.8 years reported by McCutchen, 2007) when compared to 1980s when the life expectancy was only 14 years. In the United States, approximately 30,000 people have cystic fibrosis. Around 1,000 new cases of cystic fibrosis are diagnosed each year. One child of every 3,500 is born with cystic fibrosis. In the UK, cystic fibrosis birth is about 1 in 2400 and 4% of the people are cystic fibrosis carriers. 80% of patients are diagnosed by the age of three. 10% of patients are diagnosed at the age of 18 and 3% patients are diagnosed in adulthood.