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The cystic fibrosis transmembrane conductance regulator (CFTR) protein is an integral membrane protein that functions primarily as a ligand-gated chloride ion channel (Sheppard & Welsh, 1999). It is located in the apical membrane of airway, intestinal, pancreatic, and salivary gland epithelial cells (Lewarchik et al., 2008). The protein consists of 5 domains: 2 membrane-spanning domains (MSD), 2 nucleotide-binding domains (NBD1 and 2), and 1 regulatory (R) domain (Sheppard & Welsh, 1999). The regulation of CFTR's ion gates occur after cyclic adenosine monophosphate (cAMP) activates protein kinase A (PKA), which then phosphorylates the R domain (Lewarchik et al., 2008). Subsequent binding of adenosine triphosphate (ATP) to both NBDs opens the ion channel gate while the hydrolysis of the ATP closes it (Riordan, 2008). The CFTR protein is part of a family of ATP-binding cassette (ABC) transporters, but is unique in that it is the only transporter which has an R domain and functions as an ion channel (Lewarchik et al., 2008).
Not only does CFTR function as a chloride ion channel, but it also plays a role in the regulation of other transport proteins and cellular functions (Noël et al., 2008). For example, CFTR interacts with epithelial sodium channels (ENaC) to reduce or inhibit absorption of sodium ions across the epithelia (Riordan, 2008). This further emphasizes the importance of CFTR in maintaining ion and liquid homeostasis in the apical membrane.
In a normal patient, the CFTR protein functions normally as previously described. However, in a patient without functional CFTR proteins, this results in unregulated anion transport and consequently, unregulated water transport across the epithelia (Riordan, 2008). Chloride ions cannot leave the epithelial cells and sodium ions are over-absorbed (Kreindler, 2010). Cystic fibrosis (CF) is the disease describing such a patient lacking functional CFTR proteins. Although CF causes a wide variety of symptoms, one of the most morbid symptoms affects the patient's lungs. Without the transport of water and ion molecules in the epithelia lining the airways, the mucus becomes dehydrated and accumulates in the lungs (Riordan, 2008). This leads to chronic bacterial infection resulting in inflammation and tissue damage (Riordan, 2008).
The absence of functional CFTR proteins leading to CF arises from mutations in its corresponding coding gene. Since CF is an autosomal recessive disorder, both copies of the CFTR-coding gene must be affected to display the disease phenotype (Kreindler, 2010). In other words, only one function copy of the CFTR gene is necessary to produce the functional CFTR protein. There are many different mutations which can cause CF, however, delta F508 mutation is the most prevalent (Kreindler, 2010). The delta F508 mutation is a deletion of the phenylalanine amino acid at position 508 in NBD1 of the CFTR polypeptide (Cui et al., 2006). This mutation disrupts the protein folding and maturation and so it arrests in the endoplasmic reticulum (ER). The quality control machinery present in the ER ensures that the mutant CFTR protein does not continue along the secretory pathway, but instead, is degraded (Cui et al., 2006).
The understanding of CFTR function helps us in the development of therapies for CF. One potential treatment for CF is an oral drug known as miglustat, which is an Î±-1,2- glucosidase inhibitor (Norez et al., 2006). Evidence has shown that the inhibition of glucosidase prevents the interaction of the delta F508 CFTR protein with calnexin, a chaperon molecule part of the quality control in the ER. This ultimately rescues the otherwise functional delta F508 CFTR protein from being degraded.
Many other therapies target the lung disease aspect of CF, which develops through stages of mucus retention, infection, inflammation, and tissue damage, by improving mucociliary clearance (Kreindler, 2010). Chest percussion with postural drainage or high-frequency chest wall oscillation are used to loosen the mucus from the walls of the airway to assist in clearance (Kreindler, 2010). Pharmacological therapies may lower the mucus viscosity or add a layer of water over the airway surface to allow for easier clearance of the mucus (Kreindler, 2010). The progression of lung disease can be slowed by the prevention of sodium ion over-absorption that would lead to depletion of the airway surface liquid (ASL). Hypertonic saline solution can be inhaled in order to draw water out into the lumen of the airways via osmosis (Kreindler, 2010). Since the hypertonic solution in the airways will be higher in solute concentration, water will flow out of the epithelia to even the solute concentration on either side of the apical membrane. This has been proven to improve lung function in CF patients, if only acutely (Kreindler, 2010).
Another method of treatment for CF aims to increase the secretion of fluid into the airways and mucus, which is mediated by the secretion of ions (Kreindler, 2010). The strategy is to secrete chloride ions into the airways through a pathway independent of the CFTR. Certain pharmaceutical compounds acts as agonists to stimulate chloride ion secretion. Finally, when lung disease progression is advanced, lung transplants can be used as a last resort. However, lung transplantation is a high risk-procedure which may lead to many complications and post-operative difficulties.
In conclusion, insight into the cellular and molecular role and functioning of the CFTR protein allows us to understand the underlying causes of CF symptoms. This makes it easier to develop effective therapies for CF which can target any of the different aspects of the CFTR protein.
Cui, L., Aleksandrov, L., Hou, Y., Gentzsch, M., Chen, J., Riordin, J.R., & Aleksandrov, A.A. (2006). The role of cystic fibrosis transmembrane conductance regulator phenyalanine 508 side chain in ion channel gating, Journal of Physiology, 572(2), 347-358.
This paper described what the delta F508 mutation was and provided evidence as to how the mutation impairs the functioning of CFTR.
Kreindler, J.L. (2010). Cystic fibrosis: Exploiting its genetic basis in the hunt for new therapies, Pharmacology & Therapeutics, 125, 219-229.
This paper described potential therapies for CF and how they targeted specific aspects of the disease. It described therapies for mucus clearance from the lungs, anti-inflammatory, and antimicrobial treatments.
Lewarchik, C.M., Peters, K.W., Qi, J., & Frizzell R.A. (2008). Regulation of CFTR trafficking by its R domain, The Journal of Biological Chemistry, 283(42), 28401-28412.
This paper provided information on the function of CFTR and detailed the pathway for ion transport across the apical membrane.
Norez, C., Noel, S., Wilke, M., Bijvelds, M., Jorna, H., Melin, P., DeJonge, H., & Becq, F. (2006). Rescue of functional delF508-CFTR channels in cystic fibrosis epithelial cells by the alpha-glucosidase inhibitor miglustat, Federation of European Biochemical Societies, 580, 2081-2086.
This paper discussed how the miglustat agent affects the quality control mechanism that would usually degrade the unfolded CFTR protein due to the delta F508 mutation.
Riordan, J.R. (2008). CFTR function and prospects for therapy, Annual Review of Biochemistry, 77, 701-726.
This paper described the primary role and mechanism of the CFTR channel protein as well as the other cellular activities influenced by CFTR such as sodium ion transport.
Sheppard, D.N., & Welsh, M.J. (1999). Structure and function of the CFTR chloride channel, Physiological Reviews, 79(1), 23-45.
This paper also discussed the structure and function of the CFTR protein and how it plays a role in fluid and ion secretion into the airway epithelial cells. The details associated with each of the 5 domains of CFTR were shown.
After completing this assignment, I wished that I could have split up the workload a little bit more, instead of over the past 2-3 days. I realized that reading through all of the academic literature that I found relating to the topic took longer than I expected. I also found that finding relevant and good-quality literature took me quite a while since there was a large amount of literature on CF. Even after my attempt to narrow my search, there was often over a hundred papers to scroll through. Perhaps it was just due to the sheer volume of literature, or perhaps I was unable to find an effective method of limiting my search.
Next time, I will make sure to plan well ahead for the problem summary (despite midterms) so that I do not feel as rushed in searching for relevant academic literature. I will also ask for help in online literature search if I need help.
In addition, I found that this assignment really helped me to better understand how ion channels work as well as the quality control mechanism of the ER. The knowledge that I gained through doing research and synthesizing the information that I found will most likely help me in this course, especially with the upcoming midterm.