The cystic fibrosis transmembrane conductance regulator ( CFTR ) protein is an built-in membrane protein that maps chiefly as a ligand-gated chloride ion channel ( Sheppard & A ; Welsh, 1999 ) . It is located in the apical membrane of air passage, enteric, pancreatic, and salivary secretory organ epithelial cells ( Lewarchik et al. , 2008 ) . The protein consists of 5 spheres: 2 membrane-spanning spheres ( MSD ) , 2 nucleotide-binding spheres ( NBD1 and 2 ) , and 1 regulative ( R ) sphere ( Sheppard & A ; Welsh, 1999 ) . The ordinance of CFTR ‘s ion Gatess occur after cyclic adenosine monophosphate ( camp ) activates protein kinase A ( PKA ) , which so phosphorylates the R sphere ( 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 portion of a household of ATP-binding cassette ( ABC ) transporters, but is alone in that it is the lone transporter which has an R sphere and maps as an ion channel ( Lewarchik et al. , 2008 ) .
Not merely does CFTR map as a chloride ion channel, but it besides plays a function in the ordinance of other conveyance proteins and cellular maps ( Noel et al. , 2008 ) . For illustration, CFTR interacts with epithelial Na channels ( ENaC ) to cut down or suppress soaking up of Na ions across the epithelial tissue ( Riordan, 2008 ) . This farther emphasizes the importance of CFTR in keeping ion and liquid homeostasis in the apical membrane.
In a normal patient, the CFTR protein maps usually as antecedently described. However, in a patient without functional CFTR proteins, this consequences in unregulated anion conveyance and accordingly, unregulated H2O conveyance across the epithelial tissue ( Riordan, 2008 ) . Chloride ions can non go forth the epithelial cells and Na ions are over-absorbed ( Kreindler, 2010 ) . Cystic fibrosis ( CF ) is the disease depicting such a patient missing functional CFTR proteins. Although CF causes a broad assortment of symptoms, one of the most morbid symptoms affects the patient ‘s lungs. Without the conveyance of H2O and ion molecules in the epithelial tissue run alonging the air passages, the mucous secretion becomes dehydrated and accumulates in the lungs ( Riordan, 2008 ) . This leads to chronic bacterial infection ensuing in redness and tissue harm ( Riordan, 2008 ) .
The absence of functional CFTR proteins taking to CF arises from mutants in its matching coding cistron. Since CF is an autosomal recessionary upset, both transcripts of the CFTR-coding cistron must be affected to expose the disease phenotype ( Kreindler, 2010 ) . In other words, merely one map transcript of the CFTR cistron is necessary to bring forth the functional CFTR protein. There are many different mutants which can do CF, nevertheless, delta F508 mutant is the most prevailing ( Kreindler, 2010 ) . The delta F508 mutant is a omission of the phenylalanine amino acid at place 508 in NBD1 of the CFTR polypeptide ( Cui et al. , 2006 ) . This mutant disrupts the protein folding and ripening and so it arrests in the endoplasmic Reticulum ( ER ) . The quality control machinery nowadays in the ER ensures that the mutant CFTR protein does non go on along the secretory tract, but alternatively, is degraded ( Cui et al. , 2006 ) .
The apprehension of CFTR map helps us in the development of therapies for CF. One possible intervention for CF is an unwritten drug known as miglustat, which is an I±-1,2- glucosidase inhibitor ( Norez et al. , 2006 ) . Evidence has shown that the suppression of glucosidase prevents the interaction of the delta F508 CFTR protein with calnexin, a chaperon molecule portion of the quality control in the ER. This finally rescues the otherwise functional delta F508 CFTR protein from being degraded.
Many other therapies target the lung disease facet of CF, which develops through phases of mucous secretion keeping, infection, redness, and tissue harm, by bettering mucociliary clearance ( Kreindler, 2010 ) . Chest percussion with postural drainage or high-frequency thorax wall oscillation are used to loosen the mucous secretion from the walls of the air passage to help in clearance ( Kreindler, 2010 ) . Pharmacological therapies may take down the mucous secretion viscousness or add a bed of H2O over the airway surface to let for easier clearance of the mucous secretion ( Kreindler, 2010 ) . The patterned advance of lung disease can be slowed by the bar of sodium ion over-absorption that would take to depletion of the airway surface liquid ( ASL ) . Hypertonic saline solution can be inhaled in order to pull H2O out into the lms of the air passages via osmosis ( Kreindler, 2010 ) . Since the hypertonic solution in the air passages will be higher in solute concentration, H2O will flux out of the epithelial tissue to even the solute concentration on either side of the apical membrane. This has been proven to better lung map in CF patients, if merely acutely ( Kreindler, 2010 ) .
Another method of intervention for CF purposes to increase the secernment of fluid into the air passages and mucous secretion, which is mediated by the secernment of ions ( Kreindler, 2010 ) . The scheme is to release chloride ions into the air passages through a pathway independent of the CFTR. Certain pharmaceutical compounds acts as agonists to excite chloride ion secernment. Finally, when lung disease patterned advance is advanced, lung grafts can be used as a last resort. However, lung organ transplant is a high risk-procedure which may take to many complications and post-operative troubles.
In decision, penetration into the cellular and molecular function and operation of the CFTR protein allows us to understand the implicit in causes of CF symptoms. This makes it easier to develop effectual therapies for CF which can aim any of the different facets of the CFTR protein.
Cui, L. , Aleksandrov, L. , Hou, Y. , Gentzsch, M. , Chen, J. , Riordin, J.R. , & A ; Aleksandrov, A.A. ( 2006 ) . The function of cystic fibrosis transmembrane conductance regulator phenyalanine 508 side concatenation in ion channel gating, Journal of Physiology, 572 ( 2 ) , 347-358.
This paper described what the delta F508 mutant was and provided grounds as to how the mutant impairs the operation of CFTR.
Kreindler, J.L. ( 2010 ) . Cystic fibrosis: Exploiting its familial footing in the Hunt for new therapies, Pharmacology & A ; Therapeutics, 125, 219-229.
This paper described possible therapies for CF and how they targeted specific facets of the disease. It described therapies for mucus clearance from the lungs, anti-inflammatory, and antimicrobic interventions.
Lewarchik, C.M. , Peters, K.W. , Qi, J. , & A ; Frizzell R.A. ( 2008 ) . Regulation of CFTR trafficking by its R sphere, The Journal of Biological Chemistry, 283 ( 42 ) , 28401-28412.
This paper provided information on the map of CFTR and detailed the tract for ion conveyance across the apical membrane.
Norez, C. , Noel, S. , Wilke, M. , Bijvelds, M. , Jorna, H. , Melin, P. , DeJonge, H. , & A ; 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 normally degrade the unfolded CFTR protein due to the delta F508 mutant.
Riordan, J.R. ( 2008 ) . CFTR map and chances for therapy, Annual Review of Biochemistry, 77, 701-726.
This paper described the primary function and mechanism of the CFTR channel protein every bit good as the other cellular activities influenced by CFTR such as Na ion conveyance.
Sheppard, D.N. , & A ; Welsh, M.J. ( 1999 ) . Structure and map of the CFTR chloride channel, Physiological Reviews, 79 ( 1 ) , 23-45.
This paper besides discussed the construction and map of the CFTR protein and how it plays a function in fluid and ion secernment into the airway epithelial cells. The inside informations associated with each of the 5 spheres of CFTR were shown.
After finishing this assignment, I wished that I could hold split up the work load a small spot more, alternatively of over the past 2-3 yearss. I realized that reading through all of the academic literature that I found associating to the subject took longer than I expected. I besides found that happening relevant and good-quality literature took me quite a piece since there was a big sum of literature on CF. Even after my effort to contract my hunt, there was frequently over a 100 documents to scroll through. Possibly it was merely due to the sheer volume of literature, or possibly I was unable to happen an effectual method of restricting my hunt.
Following clip, I will do certain to be after good in front for the job sum-up ( despite midterms ) so that I do non experience as rushed in seeking for relevant academic literature. I will besides inquire for aid in on-line literature hunt if I need aid.
In add-on, I found that this assignment truly helped me to better understand how ion channels work every bit good as the quality control mechanism of the ER. The cognition that I gained through making research and synthesising the information that I found will most likely assist me in this class, particularly with the approaching midterm.