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Cystic fibrosis is a hereditary disease characterized by a defective airway that causes chronic lung and digestive problems (Moskwa, 2007). It is the most common fatal genetic disease in humans (Cheng, 1990), as one in twenty-five people of European descent carry the gene for cystic fibrosis (Mayi, 2010). This gene encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which forms an epithelial chloride channel in the lungs, liver, pancreas, digestive tract, reproductive tract, and skin (Sheppard, 1999). The CFTR protein is located on the plasma membranes of cells in these organs and contains two membrane spanning domains, two nucleotide binding domains (which interact with ATP) and a regulatory domain that contains phosphorylation sites and charged amino acids (Sheppard, 1999):
The regulatory (R) domain and the nucleotide binding domains (NBD) are located on the intracellular side of the membrane. The opening and closing of the chlorine channels is highly controlled by phosphorylation and cellular ATP levels (Sheppard, 1999). Agonists from outside the cell will bind to receptors on the membrane and increase cyclic adenosine monophosphate (cAMP) levels (Mayi, 2010). cAMP will then activate protein kinase A which catalyzes the phosphorylation of multiple serine residues in the R domain (Sheppard, 1999). Once the R domain is phosphorylated, the transmembrane domains (the actual channels that chloride ions pass through) are regulated by a cycle of ATP hydrolysis at the NBD's (Sheppard, 1999). If the R domain is dephosphorylated the channel gates will close and return to their inactive state (Sheppard, 1999).
These transmembrane domains contain small, single gate channels that are selective for anions and so are permeable to chloride ions (Sheppard, 1999). Although the energy liberated by the hydrolysis of ATP is needed to open the channel, the transmembrane domains are not active transporters as the ions diffuse through the open channel following their concentration gradient. Epithelial cells that line the bodies exocrine glands and airways produce mucus and enzymes that help digest food and ensure air flow is unobstructed (Hopki, 1998). They rely on the CFTR channels to release chloride ions and water to maintain the thickness of this mucus (Hopki, 1998). The pumping of chloride ions out of the membrane results in an electrical gradient being formed, and so positively charged sodium ions will move in the same direction as the chloride ions via paracellular transport (Hopki, 1998). Because of this movement, the water potential of the mucus is reduced, and so water moves into the mucus by osmosis, resulting in increased fluidity. In epithelial cells of the sweat glands, CFTR and ENaC (epithelial sodium channel, a membrane-bound, constitutively active ion-channel that is permeable to sodium ions) are responsible for salt reabsorption (Hopki, 1998). By creating this electrochemical gradient the CFTR protein has a stimulatory effect on ENaC, as ENaC is responsible for sodium uptake from the luminal fluid, which renders it hypotonic (Mayi, 2010).
In individuals with cystic fibrosis the CFTR channel is not present and so ENaC is inhibited. Since the CFTR protein is not there to reabsorb salt, the sweat of these individuals can taste salty, (Hopki, 1998). In contrast to sweat gland cells, in all other epithelial cells the normal CFTR protein has an inhibitory effect on ENaC (Mayi, 2010). The tissue-specific functions of CFTR are further exemplified by the following diagram (Mayi, 2010):
In cystic fibrosis the epithelial cells that line the lungs and digestive tract will have increased ENaC activity (Mayi, 2010). Since chloride is not being secreted into the mucus and ENaC is active sodium uptake will be increased across the plasma membrane (Mayi, 2010). Lower salt in the mucus results in dehydration, causing a very thick and viscous mucous, containing far less water than normal (Mayi, 2010). The build up of this sticky mucus causes a myriad of problems. In the pancreas clogged passageways prevent digestive enzymes to enter the intestines, causing impaired digestion (Hopki, 1998). Mucus in the lungs clogs airways, preventing air exchange and leading to respiritory problems such as emphysema (Hopki, 1998). Individuals with cystic fibrosis have a predisposition to catching respiratory tract diseases because the mucus contains many nutrients for bacteria (such as pseudomonas aeruginosa) (Moskwa, 1998).
So what types of mutations have the ability to cause such profound symptoms? The most common mutation present in chromosome 7 of cystic fibrosis patients (70%) is âˆ†F508, where three nucleotides that code for amino acid 508, a phenylalanine, are deleted (Cheng, 1990). Patients with the âˆ†F508 mutation will produce an immature CFTR protein that does not fold correctly and which is degraded by the cell (Cheng, 1990). The endoplasmic reticulum possesses a mechanism that prevents the transport of mutant or misfolded proteins that would otherwise be destined to the Golgi for further processing (Cheng, 1990). The misfolded CFTR protein is instead dislocated to the cytosol, where
it is ubiquinated and degraded by proteosme ER associated degradation (Mayi, 2010).
If the âˆ†F508 protein was delivered to the plasma membrane, and not marked for degradation by the ER, it could still function as an active chloride channel (Mayi, 2010). A drug by the name of miglustat has been shown to correct the transfer of the mutated âˆ†F508 protein to the plasma membrane and thus restore its chloride channel function (Norez, 2006). Miglustat prevents the âˆ†F508/calnexin interaction in the ER, allowing the misfolded protein to bypass the ER's quality control mechanism (Norez, 2006). Calnexin is a "chaperone" molecule imbedded in the cytosol that allows the monitoring enzyme, glucosyl transferase, to recognize misfolded proteins (Mayi, 2010). Other drugs, such as azithromycin (an antibiotic), are necessary for cystic fibrosis patients as they are subject to frequent infections. Antibiotics prevent bacteria from growing by interfering with their ability to make proteins (Hopki, 1998). Lung transplantation also often becomes necessary as lung function and exercise tolerance declines (Fridell, 2005). Individuals with cystic fibrosis must have both lungs replaced because the remaining lung might contain bacteria that could infect the transplanted lung (Fridell, 2005). Treatments such as these, however, do not provide any long-term benefits and fall far from curing the disease. This is why it is crucial to gain a better understanding of the CFTR protein and the pathogenesis of cystic fibrosis, so that we may develop novel approaches to treat this disease and one day find a cure.