Cystic Fibrosis (CF) is an autosomal recessive genetic disorder affecting a large proportion of the Caucasian population in North America (Rowe et al., 2005). The disease is characterized by the production of thick mucus in the epithelial cells of many organs including the lungs, liver and pancreas (Rowe et al., 2005). This leads to a variety of symptoms and associated conditions including respiratory infections, lung disease, pancreatic damage and a multitude of other chronic infections (Rowe et al., 2005). This paper will focus on the specific mutation that causes CF and its effect on the plasma membrane as well as several therapies for CF. This paper aims to outline the link between changes in the plasma membrane and the symptoms of CF.
The cause of CF is a deficiency of functional Cystic Fibrosis Transmembrane conductance regulator (CTFR) protein (Cheng et al., 1990). The CFTR gene encodes this protein, and it is mutations in this gene that result in Cystic Fibrosis (Cheng et al., 1990). In the cells of healthy individuals, the CFTR protein acts as a chloride ion channel, exchanging chloride (as well as thiocyanate) ions between epithelial cells and surrounding mucous (Rowe et al., 2005). Normally, the net movement of these ions is out of the epithelial cells. The resulting electrochemical gradient allows sodium ions (positively charged) to also flow out of the epithelial cells through the epithelial Na channel (ENaC) (Clancy et al., 2005). Water in turn, is also drawn out of the epithelial cells, following the movement of sodium and chloride ions (Clancy et al., 2005). The movement of water molecules into the mucus causes it to be dilute and less viscous (Clancy et al., 2005). The CFTR protein ion channel is activated through a cyclic adenosine monophosphate (cAMP) pathway (Cheng et al., 1990). Cyclin A, whose concentration is regulated by the binding of specific agonists to epithelial cells, is responsible for the activation of protein kinase A, which phosphorylates specific sites on the regulatory domain of the CFTR protein (Anderson et al., 1991). The protein also has two nucleotide binding domains involved in the hydrolysis of ATP (Muallem and Vergani, 2009). ATP binds to binding sites within the channel, causing the formation of a nucleotide dimer (Muallem and Vergani, 2009). This dimer dissociates when ATP is hydrolyzed, triggering a conformational change in the protein that allows it to open and close, allowing chloride ions to pass through (Muallem and Vergani, 2009). Thus the activation of the CFTR protein requires two events: ATP hydrolysis as well as activation by protein kinase A. (Anderson et al. 1991). In normal cells, this is how chloride ion levels are regulated. In the case of CF however, this mechanism is disrupted by mutation.
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There are many different mutations to the CFTR gene that can cause CF, however the most common is the deltaF508 Mutation (Antigny et al., 2008). This mutation causes a deletion of three nucleotides at the 508th position of the CFTR protein, resulting in the loss of the amino acid Phenylalanine (Antigny et al., 2008). Normal CFTR proteins are synthesized in the ER and then move to the Golgi Complex, through transport vessicles and eventually arrive at the plasma membrane (Dejaard et al., 2004). Without phenylalanine however, the mutated protein does not fold correctly and as a result, normal protein trafficking is disrupted (Dejaard et al., 2004). GT, an enzyme involved in the ER quality control system, recognizes the misfolding and adds a glucose back to the protein causing it to be re-cycled through the quality control cycle before eventually being ubiquitinated and destroyed in the proteosome (Degaard et al., 2004). This results in little or no CFTR protein being produced. As a result, chloride ion movement out of the epithelial cells is drastically reduced, which in turn decreases the movement of both sodium ions and water molecules into the mucus (Rowe et al., 2005). This results in a thicker, more viscous from of mucous that accumulates in airways and around organs resulting in the variety of symptoms and associated conditions experienced by CF patients (Rowe wt al., 2005). Although there is currently no cure for the disease, research is being done on different treatments.
Many treatments for CF target the chloride ion channels in order to at least partially restore function. Current research is being done on therapies that activate alternate ion channels. A study done by Grasemann at el (2007) tested the affect of Moli1901 on individuals with CF. This peptide is thought to be capable of activating alternate chloride ion channels by increasing calcium release from intracellular stores in the epithelium (Grasemann et al., 2007). Increased calcium ion concentration has been found to indirectly activate chloride ion channels; although the mechanism is not fully understood (Clancy et al., 1990). Increasing calcium ion concentrations may be one possible therapy for CF, as it allows for alternate chloride ion transport, however there are other treatments.
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As it has been found that the mutant CFTR protein still has some functionality as a chloride ion channel, research is being done on potential therapies to overcome the trafficking defect of the mutant protein (Norez et al., 2009). If we can increase normal protein trafficking to the plasma membrane, this could be an effective therapy. Research has been done on Miglustat, a1,2-glucosidase inhibitor thought to disrupt interactions between calnexin, an enzyme involved in the ER quality control system, and mutant CFTR proteins. This results in the mutant proteins being able to pass through the quality control cycle in the ER and reach the plasma membrane where they can function as chloride ion channels (Norez et al., 2009).
Cystic Fibrosis is caused by mutations to the CFTR gene. The most common mutation involves the F508 deletion, resulting in the loss of an amino acid and misfolding, causing the proteins to be destined for destruction in the protesome. Although there is no cure for CF, research is being done on treatments aimed to restore chloride ion channel activity by either activating alternative channels or bypassing the ER quality control system. Because CF is such a prominent disease and has such a variety of fatal symptoms, research into treatments is very important. Although treating the symptoms alone can prolong the lives of patients, therapies like Miglustat and Moli1901 that are aimed to target the root of the problem, the CFTR ion channels, would likely be more effective.
Literature Cited/ Annotated References
Anderson, M.P., Berger, H.A., Rich, D.P., Gregory, R.J., Smith, A.E. and Welsh, M.J. (1991). Nucleoside Triphosphates are Required to Open the CFTR Chloride Channel. Cell. 67: 775-784.
This paper details how the CFTR channel is activated by Protein Kinase A as well as by the binding of ATP to specific sites within the channel. It explains how both events are necessary In order to activate the CFTR channel for chloride ion transport across epithelial cells.
Antigny, F., Norez, C., Cantereau, A., Becqm F. and Vandebrouck, C. (2008). Abnormal spatial diffusion of Ca.sup.2+ .sup.in F508del-CFTR airway epithelial cells. Respiratory Research.Â 9(70): 70.
This paper outlines the three nucleotide F508del in the CFTR protein, the most common mutation causing CF, and its effect on the CFTR protein. Phenylalanine is lost from the protein resulting in incorrect folding which leads to destruction of the mutant protein.
Cheng, S.H., Gregory, R.J., Marshall, J., Paul, S., Souza, D.W., White, G.A. (1990). Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell.63: 827-834.
This paper explains the isolation of the CFTR protein and the relation between Cystic Fibrosis and mutations to this gene. The cAMP pathway, and subsequent activation of the CFTR gene is also described.
Clancy, J., McCann, J., Li, M. and Welsh. M. (2005)Calcium-Dependent Regulation of Airway Epithilial Chloride Channels. American Journal of Physiology- Lung, Cellular and Molecular Biology. 258(2): 25-32.
This paper provides specific details for the hypothesis that calcium ion concentration in the cell can indirectly regulate chloride ion channel activity.
Dejgaard, S., Nicolay, J., Taheri, M., Thomas, D.Y. and Bergeron, J.M. (2004. The ER Glycoprotein Quality Control System. Current Issues in Molecular Biology. 6: 29-42. This paper explains the roles of the various enzymes involved in the quality control system in the ER. It explains the process by which misfolded proteins are detected by GT and either corrected o sent to the proteosome for destruction.
Grasemann, H., Stehling, F., Brunar, H., Widmann, R., Laliberte, T.W., Molina, L., Doring, G. and Ratjen, F. (2007). Inhalation of Moli1901 in Patients with Cystic Fibrosis. Chest. 131(5): 1461-1466.
This paper provides evidence that Moli1901, a peptide can be used to treat cystic fibrosis as it increases intracellular calcium levels. This increase in calcium ions is able to increase chloride ion transport out the epithelial cells as well as the resulting movement of water molecules.
Muallem, D. and Vergani, P. (2009). ATP hydrolysis-driven gating in cystic fibrosis transmembrane conductance regulator. Philosophical Transactions of the Royal Society B: Biological Sciences. 364(1514): 247-255.
This paper explains the binding of ATP to the CFTR protein channel. Dimers are formed upon the bidning of ATP and when ATP is hydrolyzed, a conformational change allows ions to move through the channel.
Norez, C., Antigny, F., Noel, S., Vandebrouck, C and Becq, F. (2009). A CF Resporatory Epithelial Cell Chronically Treated by Miglustat Acquires a Non-CF Like Phenotype. American Journal of Respiratory Cellular Molecular Biology. 41(2): 217-225.
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This paper provides data to support the claim that Miglustat can be used to treat Cystic Fibrosis patents as it increases calcium release in intracellular spaces.
Rowe, S.M., Miller, S. and Sorscher, R.J. (2005). Cystic Fibrosis. New England Journal of Medicine. 352(19):1992-2001.
This paper provides information on the basic etiology of Cystic Fibrosis. It explains the genetic basis if heritability as well as the symptoms and conditions arising from the disease.