The Effect Of Cystic Fibrosis On Plasma Membrane Biology Essay

Cystic Fibrosis ( CF ) is an autosomal recessionary familial upset impacting a big proportion of the Caucasic population in North America ( Rowe et al. , 2005 ) . The disease is characterized by the production of thick mucous secretion in the epithelial cells of many variety meats including the lungs, liver and pancreas ( Rowe et al. , 2005 ) . This leads to a assortment of symptoms and associated conditions including respiratory infections, lung disease, pancreatic harm and a battalion of other chronic infections ( Rowe et al. , 2005 ) .

This paper will concentrate on the specific mutant that causes CF and its consequence on the plasma membrane every bit good as several therapies for CF. This paper aims to sketch the nexus between alterations in the plasma membrane and the symptoms of CF.The cause of CF is a lack of functional Cystic Fibrosis Transmembrane conductance regulator ( CTFR ) protein ( Cheng et al. , 1990 ) . The CFTR cistron encodes this protein, and it is mutants in this cistron that consequence in Cystic Fibrosis ( Cheng et al. , 1990 ) .

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In the cells of healthy persons, the CFTR protein acts as a chloride ion channel, interchanging chloride ( every bit good as thiocyanate ) ions between epithelial cells and environing mucose ( Rowe et al. , 2005 ) . Normally, the net motion of these ions is out of the epithelial cells.

The ensuing electrochemical gradient allows Na ions ( positively charged ) to besides flux out of the epithelial cells through the epithelial Na channel ( ENaC ) ( Clancy et al. , 2005 ) . Water in bend, is besides drawn out of the epithelial cells, following the motion of Na and chloride ions ( Clancy et al. , 2005 ) . The motion of H2O molecules into the mucous secretion causes it to be dilute and less syrupy ( Clancy et al. , 2005 ) . The CFTR protein ion channel is activated through a cyclic adenosine monophosphate ( camp ) tract ( 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 regulative sphere of the CFTR protein ( Anderson et al. , 1991 ) . The protein besides has two nucleotide adhering spheres involved in the hydrolysis of ATP ( Muallem and Vergani, 2009 ) . ATP binds to adhering sites within the channel, doing the formation of a nucleotide dimer ( Muallem and Vergani, 2009 ) . This dimer dissociates when ATP is hydrolyzed, triping a conformational alteration in the protein that allows it to open and shut, leting chloride ions to go through through ( Muallem and Vergani, 2009 ) .

Thus the activation of the CFTR protein requires two events: ATP hydrolysis every bit good as activation by protein kinase A. ( Anderson et al. 1991 ) . In normal cells, this is how chloride ion degrees are regulated.

In the instance of CF nevertheless, this mechanism is disrupted by mutant.There are many different mutants to the CFTR cistron that can do CF, nevertheless the most common is the deltaF508 Mutation ( Antigny et al. , 2008 ) . This mutant causes a omission of three bases at the 508th place of the CFTR protein, ensuing in the loss of the amino acerb Phenylalanine ( Antigny et al. , 2008 ) .

Normal CFTR proteins are synthesized in the ER and so travel to the Golgi Complex, through conveyance vessicles and finally arrive at the plasma membrane ( Dejaard et al. , 2004 ) . Without phenylalanine nevertheless, the mutated protein does non turn up right and as a consequence, 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 doing it to be re-cycled through the quality control rhythm before finally being ubiquitinated and destroyed in the proteosome ( Degaard et al. , 2004 ) . This consequences in small or no CFTR protein being produced. As a consequence, chloride ion motion out of the epithelial cells is drastically reduced, which in bend decreases the motion of both sodium ions and H2O molecules into the mucous secretion ( Rowe et al. , 2005 ) . This consequences in a thicker, more syrupy from of mucose that accumulates in air passages and around variety meats ensuing in the assortment of symptoms and associated conditions experienced by CF patients ( Rowe wt al.

, 2005 ) . Although there is presently no remedy for the disease, research is being done on different interventions.Many interventions for CF target the chloride ion channels in order to at least partly restore map. Current research is being done on therapies that activate alternate ion channels. A survey done by Grasemann at EL ( 2007 ) tested the affect of Moli1901 on persons with CF.

This peptide is thought to be capable of triping alternate chloride ion channels by increasing Ca release from intracellular shops in the epithelial tissue ( Grasemann et al. , 2007 ) . Increased Ca ion concentration has been found to indirectly trip chloride ion channels ; although the mechanism is non to the full understood ( Clancy et al. , 1990 ) .

Increasing Ca ion concentrations may be one possible therapy for CF, as it allows for surrogate chloride ion conveyance, nevertheless there are other interventions.As it has been found that the mutant CFTR protein still has some functionality as a chloride ion channel, research is being done on possible therapies to get the better of 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 effectual therapy. Research has been done on Miglustat, a1,2-glucosidase inhibitor thought to interrupt interactions between calnexin, an enzyme involved in the ER quality control system, and mutant CFTR proteins. This consequences in the mutant proteins being able to go through through the quality control rhythm in the ER and make the plasma membrane where they can work as chloride ion channels ( Norez et al. , 2009 ) .Cystic Fibrosis is caused by mutants to the CFTR cistron. The most common mutant involves the F508 omission, ensuing in the loss of an amino acid and misfolding, doing the proteins to be destined for devastation in the protesome. Although there is no remedy for CF, research is being done on interventions aimed to reconstruct chloride ion channel activity by either triping alternate channels or short-circuiting the ER quality control system.

Because CF is such a outstanding disease and has such a assortment of fatal symptoms, research into interventions is really of import. Although handling the symptoms entirely can protract the lives of patients, therapies like Miglustat and Moli1901 that are aimed to aim the root of the job, the CFTR ion channels, would probably be more effectual.Literature Cited/ Annotated MentionsAnderson, 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 inside informations how the CFTR channel is activated by Protein Kinase A every bit good as by the binding of ATP to specific sites within the channel. It explains how both events are necessary In order to trip the CFTR channel for chloride ion conveyance across epithelial cells.Antigny, F.

, Norez, C. , Cantereau, A. , Becqm F. and Vandebrouck, C. ( 2008 ) . Abnormal spacial diffusion of Ca.sup.2+ . F508del-CFTR airway epithelial cells. Respiratory Research. & A ; Acirc ; 9 ( 70 ) : 70.This paper outlines the three nucleotide F508del in the CFTR protein, the most common mutant doing CF, and its consequence on the CFTR protein.

Phenylalanine is lost from the protein ensuing in incorrect folding which leads to devastation of the mutant protein.Cheng, S.H. , Gregory, R.J. , Marshall, J. , Paul, S. , Souza, D.

W. , White, G.A. ( 1990 ) . Defective intracellular conveyance and processing of CFTR is the molecular footing of most cystic fibrosis. Cell.63: 827-834.This paper explains the isolation of the CFTR protein and the relation between Cystic Fibrosis and mutants to this cistron.

The camp tract, and subsequent activation of the CFTR cistron is besides 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 inside informations for the hypothesis that Ca ion concentration in the cell can indirectly modulate 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 functions of the assorted enzymes involved in the quality control system in the ER. It explains the procedure by which misfolded proteins are detected by GT and either corrected o sent to the proteosome for devastation.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 grounds that Moli1901, a peptide can be used to handle cystic fibrosis as it increases intracellular Ca degrees.

This addition in calcium ions is able to increase chloride ion conveyance out the epithelial cells every bit good as the ensuing motion of H2O molecules.Muallem, D. and Vergani, P. ( 2009 ) . ATP hydrolysis-driven gating in cystic fibrosis transmembrane conductance regulator. Philosophic Minutess 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 alteration allows ions to travel 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.

This paper provides informations to back up the claim that Miglustat can be used to handle Cystic Fibrosis patents as it increases Ca release in intracellular infinites.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 familial footing if heritability every bit good as the symptoms and conditions originating from the disease.


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