Cystic fibrosis Flashcards
What is the CFTR protein and where is it found?
CFTR protein is encoded for by the cystic fibrosis transmembrane regulator gene- found on the long arm of chromosome 7 and is comprised of 27 exons. The gene encodes CFTR protein which is a multidomain chloride ion channel.
Describe the structure of the CFTR protein
CFTR protein has two nuclear binding domains (NBD1 and NBD2), two membrane spanning domains (MSD1 and MSD2) and a regulatory domain (R) domain which is the site of ATP phosphorylation.
Where is the F508 CFTR mutation located?
Is located on the NBD1 and causes kinetic and thermodynamic changes to NBD1
How is the CFTR pore formed?
Two transmembrane domains, each comprising six transmembrane helices, form the pore of the chloride channel and are connected by cystosolic loops (CL1 and CL2) and extracellular loops. NBD1 and NBD2 form a head to tail dimer which forms two composite ATP binding sites at their interface.
Describe how the chloride channel is opened
Typically opens when ATP docks in the ATP binding site on each NBD. In channels that have been activated by protein kinase A dependent phosphorylation of the R domain, binding of the two ATP molecules causes dimerisation of the two NBDs, triggering channel opening. Hydrolysis of one of these ATP molecules may then cause channel closing, followed by the release of hydrolysis products and at least partial dimer dissociation
Describe the structure of the lungs in a healthy person
Airway surface liquid (ASL) found on the top of epithelial cells in the lungs, functions to move inhaled particles away from the surface of the lungs and into the stomach to be broken down. The ASL is composed of two layers, the periciliary layer that extends from the cell surface to the height of the extended cilium and the mucus layer, which is positioned on top of the cilia.
This gel provides a low friction environment for effective lubricant activity; mucus layer is composed of a long, highly glycosylated polymers known as secreted mucins which trap and retain inhaled particles
How do normal lungs absorb sodium?
Cells both absorb and secrete ions, allowing water to move osmotically in response in response to gradients generated. Active transport of Na+ ions is mediated by a rate limiting channel in the apical membrane, (ENaC) and it removed sodium from the cell with an ATPase
What happens in CF patients to cause dehydration of the ALS?
The absence or non-function of CFTR at the membrane causes unregulated Na+ absorption and a decreased capacity to secrete Cl-. The combination of these two affects means that there is dehydration of the ALS and a collapse of the periciliary layer, causing a concentration of mucus in the mucus layer and adhesion of mucus to the airway surface. This means that bacteria and mucus cannot be sent to the stomach.
What is Ivacaftor?
Good potentiator of most CFTR mutations
Causes CFTR to open more frequently and for longer
Increases open probability of F508 mutation and wild-type CFTR
What was shown in the clinical trials of Ivacaftor?
ΔG551D patients treated with Ivacaftor showed a 10%/per week increase in lung function which was sustained over 52 weeks
Patients showed a decreased amount of exacerbations
Improved mucociliary clearance in patients
Caused the disappearance of mucus plugs
What is Lumacaftor?
Is a treatment that was developed to try and treat F508 patients- showed good efficacy in the clinic but did not work well in patients- however, when combined with Ivacaftor (kalydeco) showed efficacy for patients which are F508 homozygotes
