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Cystic Fibrosis Signaling Pathway
Transcript of Cystic Fibrosis Signaling Pathway
Over 1,000 different mutations have been identified that can cause CF
The most common mutation is F508 that occurs when an error in transcription deletes 1 amino acid (phenylalanine)
The resulting peptide chain cannot fold correctly and does not open to allow an ATP molecule to enter the NBD complex
Therefore, chloride ions do not exit the epithelial cell (Anderson, n.d.)
Basics of Cystic Fibrosis
an inherited genetic disease that affects the lungs and digestive system
most common lethal genetic disease in the US, affecting 30,000 children and adults (Reece, 2011, p. 277)
CF only occurs in individuals that are homozygous recessive
1 in 31 Americans (10 million people) carry a defective CF gene
4% of Americans of European ancestry are heterozygous for cystic fibrosis ("About Cystic Fibrosis," n.d.)
by Sarah Kulesa and Jack McKenzie
The three main organs affected by CF are the lungs, pancreas, and small intestine.
frequent lung infections
wheezing, shortness of breath
salty tasting skin
CF is diagnosed through a sweat test that measures excessively high concentrations of chloride anions ("About Cystic Fibrosis," n.d.)
calcitonin gene-related peptide (CGRP) ligand bonds to the G protein-coupled receptor (Anderson, n.d.)
G protein-coupled receptor phosphorylates a GDP molecule on the G protein
G protein activates adenylyl cyclase, which converts ATP to cAMP
cAMP activates protein kinase A (PKA), which transducts the cellular signal to the cystic fibrosis transmembrane conductance regulator (CFTR) (Berridge, 2010)
Cell Signaling Pathway
PKA phosphorylates the R group of the amino acid chain, causing it to interact with the N terminus
The interaction allows the two identical halves of the nucleotide-binding domain (NBD) to attract an ATP molecule and close
the presence of the ATP causes a conformational change in the protein's shape, causing the a-helices to create a pore
chloride anions can enter/exit through the pore
once hydrolyzed, the ATP molecule leaves the CFTR and the pore closes (Berridge, 2010)
The CFTR channel allows chloride ions to flow between the extracellular fluid and the cytoplasm, creating an electrochemical gradient that contributes to the osmotic flow of water. When the cell signaling pathway malfunctions, the CFTR channels don't allow chloride ions to exit the cell. Water molecules diffuse into the cell to dilute the excess chloride concentration, dehydrating the mucus covering the epithelial cells in the lungs. The thicker mucus immobilizes the cell's cilia so that inhaled debris cannot be coughed up, resulting in numerous bacterial lung infections (Wine, 2003).
Effects on Other Organs
In patients with CF, the pancreas is gradually destroyed and replaced by fibrous cysts (hint "cystic fibrosis") because the ducts leading from the pancreas become clogged with mucus, inhibiting enzymes from reaching the digestive system
CF patients experience chronic constipation because the small intestines can't secrete sufficient fluid to transport bowel movements (Wine, 2003)
Recent studies have suggested that the CFTR channels may be involved in the regulation of epithelial sodium channels (ENaC). Normally, CFTR channels permit the ENaC to allow Na ions to enter/exit the cell. When the CFTR is mutated, however, the ENaC cannot close, resulting in hyperabsorbtion of Na ions that are attracted to the Cl ions. This exacerbates the diffusion of water into the cell, further dehydrating the mucus (Berridge, 2010).
Also, research indicates that in sweat glands CFTR inhibits Cl ions from entering the cell, producing the high Cl ion concentration in the sweat of CF patients ("About Cystic Fibrosis, n.d.)
About Cystic Fibrosis. (n.d.). Retrieved November 2, 2013, from Cystic Fibrosis Foundation website: http://www.cff.org/aboutcf/
Anderson, R. (n.d.). Cystic Fibrosis Transmembrane Conductance Regulator And Beta 2 Adrenergic Receptor Pathway. Retrieved November 2, 2013, from Biocarta website: http://www.biocarta.com/pathfiles/h_cftrPathway.asp
Berridge, M. (2010). Cystic Fibrosis Transmembrane Conductance Regulator. Retrieved November 2, 2013, from Biochemical Jounral website: http://www.biochemj.org/csb/frame.htm
Reece, J. B., Urry, L. A., Cain, M. L., Wasserman, S. A., Minorsky, P. V., & Jackson, R. B. (2011). Cystic Fibrosis . In Campbell Biology (9th ed., p. 277). San Francisco , CA: Pearson Benjamin Cummings.
Wine, O. J. (2003). Human Genome- Cystic Fibrosis. Retrieved November 2, 2013, from Stanford University website: http://www.stanford.edu/class/psych121/humangenome-CF.htm#sweat