Cystic fibrosis (CF) is a common autosomal recessive disorder that is caused by the defective gene encoding Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) (Zielenski et al., 1991). CFTR is a chloride ion channel found in the lumen-facing (apical) membrane of epithelial cells, in which it participates in regulation of salt and water transport across epithelial tissues (Cheng et al., 1990). In majority of CF patients, absence or dysfunction of CFTR protein promotes bacterial growth in the CF lung (Aigner et al., 2008). This paper will focus on what CFTR is and its role in CF development in the lungs, as well as possible treatments of CF.
The CFTR is Protein kinase A (PKA) activated chloride channel at the apical membrane of epithelial cells (Berger, Travis, & Welsh., 1993). CFTR protein is made up of 5 domains: two membrane-spinning domains (MSD1 and MSD2) that form the chloride ion channel, two nucleotide binding domains (NBD1 and NBD2) that bind and hydrolyze ATP, and a regulatory (R) domain (Berger et al., 1993). In the Endoplasmic Reticulum (ER), CFTR is synthesized and assembled by chaperone molecules (calnexin in particular), which they assist in polypeptide folding into a protease resistant conformation (Cheng et al., 1990). Following N-glycosylation, CFTR is transported to Golgi apparatus for additional processing before being integrated into the cell membrane to function as a chloride channel (Cheng et al., 1990). In case of CF, many patients have deleted Phenylalanine in the NBD1 sequence of CFTR gene, which is called delta F508 (Zielenski et al., 1991). This mutant CFTR loses its ability to fold into its protease resistant form. The misfolded CFTR is then recognized by the quality-control mechanism in the ER (Cheng et al., 1990). Calnexin retains misfolded or incompletely assembled proteins in the ER and thus plays a main role in mislocalization of delF508 CFTR (Pind et al., 1994). Though delF508 CFTR is not functionally impaired, chaperone molecules mislocalize the protein product and ultimately degrade it via ubiquitin-dependent pathway (Cheng et al., 1990; Pind et al., 1994). As a result, delF508 CFTR does not attain mature glycosylation state that can get transported to Golgi apparatus and can never proceed further to its functional site at the cell surface (Cheng et al., 1990).
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CFTR plays a vital role in anion flow for normal function of epithelia. Once embedded in the plasma membrane, phosphorylation or dephosphorylation of R domain regulates CFTR for the movement of Cl- across the plasma membrane (Berger et al., 1993). As Cl- accumulate near positively charged regions of CFTR, R domain is phosphorylated by PKA. Then NBD1 and NBD2 hydrolyze ATP and form a stable intramolecular heterodimer-like interaction that opens up the chloride channel (Csanády et al., 2005). Upon opening of a channel, Cl- flow down the electrochemical gradient into the mucus layer. As a result, water also moves out of the epithelial cell to hydrate the mucus layer (Cheng et al., 1990). This mechanism for keeping mucus layer hydrated is extremely important to keep the lungs healthy, because cilia sweep the mucus away from the lungs (Cheng et al., 1990). Overall, the Cl- flow out of the epithelial cells via CFTR is necessary to keep mucus layer hydrated for mucociliary clearance. Therefore, without CFTR at apical membrane, impaired anion flow causes accumulation of mucus in the lung that initiates bacterial infection (Cheng et al., 1990; Aigner et al., 2008).
Disruption of CFTR function alters the salt and water content of luminal secretions and impairs airway mucosal defense. CFTR functions as a chloride channel, but it also regulates other channels in the airway epithelial cells (Csanády et al., 2005). CFTR inhibits epithelium sodium channels (ENaCs) during activation of chloride ion secretion in order to maintain a low intracellular Na+ concentration (Csanády et al., 2005). CFTR also stimulates ORCCs for chloride ion secretion to the extracellular surface of airway epithelia (Cheng et al., 1990). During times of secretion, ORCC open up and Cl- exit down its electrochemical gradient into the mucus (Aigner et al., 2008). Cl- is followed by Na+ and water due to the resulting osmotic gradient across the plasma membrane, thus hydrating the mucus. However, absent or reduced CFTR and inactivated ORCCs in CF airways makes it impossible for Cl- to escape out of the cell (Csanády et al., 2005). Moreover, unsuppressed ENaC allows high concentration of Na+ to travel back into the cells of the airway. As a result of ion imbalance across the plasma membrane, water is reabsorbed back to the epithelial cells (Csanády et al., 2005). The mucus dehydration leads epithelial cells to produce abnormally thick and sticky mucus that hinders mucociliary clearance (Cheng et al., 1990). Uncleared bacteria or germs trapped in the thick mucus leads to bacterial infection, which ultimately causes bronchial inflammation and airway obstruction (Aigner et al., 2008). This understanding of the different molecular mechanism of CFTR dysfunction can help development of therapies that increases patients' quality of life and life span.
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A better understanding of how the CFTR defect produces CF lung disease has led for the development of multiple therapies. Lung transplantation is a possible treatment for patients with advanced lung disease. However, the median survival for adults after lung transplantation is only 6.4 years (Aigner et al., 2008). Also, the therapy is irreversible, highly invasive, and it is faced with considerable growing in discrepancy between organ need and availability (Aigner et al., 2008). Fortunately, however, the possible rescue of functional delF508 CFTR by Miglustat is on the horizon. Miglustat was shown to prevent the interaction between delF508 CFTR and calnexin, a chaperone molecule that plays an important role in its ER retention (Pind, Riordan, & Williams., 1994). In case of rescue, functional delF508 CFTR in epithelial cells can regulate the amount of salt and water in airway mucus layer, which can restore mucociliary clearance of the lungs (Pind et al., 1994). The possibility of cure for CF exists if Miglustat interferes with delF508 CFTR-calnexin interaction to permit trafficking of delF508 CFTR to the plasma membrane.
CFTR is a chloride channel that regulates anion flow and modulates other conductances, such as ENaCs and ORCCs. In most cases of CF, the number of CFTR at apical membrane is greatly reduced or absent. As a result, the airway mucus thickens and the lung becomes vulnerable for bacterial infection and chronic lung disease. Overall, the studies about the structure and function of CFTR are crucial for a better understanding of the defects involved in CF and for the development of alternative therapies for this complex human disease.
Aigner, C., Jaksch, P., Taghavi, S., Lang, G., Hoda, A., Wisser, W., et al. (2008). Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases. The Journal of Heart and Lung Transplantation, 27, 60-65.
This article presented lung transplantation as a plausible approach for treating chronic lung disease. The results showed long-term survival rates in the range of primary lung transplantation for patients with advanced bronchiolitis obliterans syndrome and airway problems.
Anderson, D. (1938). Cystic fibrosis of the pancreas and relation to celiac disease: a clinical and pathologic study. American Journal of Diseases of Children, 56, 344-399.
The CF of the pancreas was first described by Anderson. She described that most of her patients produced extremely viscous secretions that led to blockage of ducts and airways. Anderson also realized that CF syndrome is based on genetics.
Berger, H., Travis, S., & Welsh, M. (1993). Regulation of the cystic fibrosis transmembrane conductance regulator Clâˆ’ channel by specific protein kinases and protein phosphatases. The Journal of Biological Chemistry, 268, 2037-2047.
In this study, CFTR was shown to be a chloride channel that is directly regulated by phosphorylation and dephosphorylation of R domain by PKA.
Cheng, S., Gregory, R., Marshall, J., Paul, S., Souza, D., White, G., et al. (1990). Defective intracellular transport and processing of CFTR is the molecular basis of most cystic fibrosis. Cell, 63, 827-834.
This paper shows that the main cause of Cystic Fibrosis is due to absent CFTR protein at apical epithelial cells.
Csanády, L., Chan, K., Nairn, A., & Gadsby, D. (2005). Functional roles of nonconserved structural segments in CFTR's NH2-terminal nucleotide binding domain. The Journal of General Physiology, 125, 43-55.
This article shows the role of NBDs in channel gating. Stabilized heterodimer-like interaction between two NBDs prolongs the channel opening to allow anions to flow down their concentration gradient across the plasma membrane of epithelial cells.
Pind, S., Riordan, J., & Williams, D. (1994). Participation of the Endoplasmic Reticulum chaperone Calnexin (p88, IP9) in the biogenesis of the Cystic Fibrosis Transmembrane Conductance Regulator. The Journal of Biological Chemistry, 269 (17), 12784-12788.
This study shows the success of trafficking functional delF508 CFTR into plasma membrane by using Miglustat. The success of Miglustat in treating CF was due to interfering with calnexin-delF508 CFTR interaction in the ER.
Quinton, P. (1983). Chloride impermeability in cystic fibrosis. Nature, 301, 421-422.
This study showed chloride impermeability in CF epithelial cells. Quinton also concluded that CFTR chloride channel could be activated by PKA in normal but not in CF airway epithelium.
Ramjeesingh M, Li, C., Garami, E., Huan, L., Galley, K., Wang, Y., & Bear, C. (1999). Walker mutations reveal loose relationship between catalytic and channel gating activities of purified CFTR (cystic fibrosis transmembrane conductance regulator). Biochemistry, 38 (5), 1463-1468.
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The article studies mechanism governing the opening and closing (gating) of the CFTR chloride channels. The results showed that NBDs participate in closing of the gate.
Wilkinson, D., Strong, T., Mansoura, M., Wood, D., Smith, S., Collins, F., et al. (1997). CFTR activation: additive effects of stimulatory and inhibitory Phosphorylation sites in the R domain. AJP - Lung Cellular and Molecular Physiology, 273, L127-L133
This study investigates individual sites within the R domain of CFTR that contributes differently to chloride channel gating.
Zielenski, J., Rozmahel, R., Bozon, D., Kerem, B., Grzelczak, Z., Riordan, J., et al. (1991). Genomic DNA sequence of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Genomics, 10, 214-228.
This study shows that the CF is a genetic disease caused by mutations in the CFTR gene, located on chromosome 7. In most cases, delta F508 is the cause of CF development.
The first challenge in this assignment was developing a relevant question to our lessons. Synthesizing a question for the assignment required thorough understanding about the specific role of CFTR in CF development. Deciding which piece of information is most important and relevant to this paper, was not easy. I tried to pick out the most important points about CF for this paper after investigating and interpreting many journal articles. Overall, the assignment gave a chance to learn and understand the lecture materials reading from various sources. Researching on my own was much more effective in learning than passive acquisition of facts transmitted from others. On the whole, I gained meaningful knowledge through my own learning process or strategy.