Question

The CFTR protein is a ABC transporter protein that functions at the plasma membrane of epithelial cells. Numerous mutations in the CFTR gene that have been associated with the disease cystic fibrosis (CF). The most common CF-causing mutation is deletion of phenylalanine 508 (F508del). This mutation causes the CFTR protein to misfold such that it is degraded as soon as it is made. The protein fails to be targeted to the plasma membrane, the required location for proper function.
Some of the symptoms observed in CF patients are:
i. thick mucus secretions in the lungs (due to a lack of water secretion from epithelial cells into the lung airway space)
ii. blocked pancreatic ducts due to thick mucus secretions

a. What is the normal function of the CFTR protein?
b. Why do mutations in the CFTR protein result in the thick mucus secretions?
c. Which classes of CF drugs can treat patients with F508del CFTR mutations?

Answer 1

Answer and Explanation:

• The normal function of the CFTR protein is to transport Cl- ions as it works as a chlorine channel regulated by AMPc and by protein kinase K (PKA). CFTR is also a regulator for other ionic channels. The CFTR protein expresses in the luminal portion of the secretory and absorptive epithelial membranes and they have an important role in the secretion of electrolytes activated by AMPc and intracellular calcium. This protein constitutes the way out of Cl-from the lumen. Apart from its secretory function, CFTR protein also regulates the function of the electrolyte by inhibiting the epithelial Na+ channel activity in absorptive epithelial cells from the colon and aerial vias, and by activating the Na+ channel in sudoriparous conducts.

• Given that defects on the CFTR protein take to a defective regulation in the Na+ channel, the cystic fibrosis characterizes for alterations in electrolytes secretions and absorption.  There are two important physiopathological mechanisms:

1) altered Cl- secretion in submucous glands,

2) increased Na+ absorption and consequent electrolytes hyperabsorption in the superficial epithelium.  

Patients with cystic fibrosis are incapable of increasing their secretory transport. On the contrary, the increased epithelial Na+ conductance in apical membranes, the paracellular permeability to Cl- and elevated permeability to water, all together, do not allow a higher osmotic transepithelial gradient, which leads to a hyperabsorption in the patient epitheliums.  The superficial liquid layer in the aerial vias decrease, mucous glands are not released from the mucus and the mucociliary clearance is strongly altered in aerial vias.

• The Lumacaftor (VX-809) is a drug directed to type II mutations. These mutations are present in an elevated number of patients with CF and include Phe508del that is the most frequent mutation. Ivacaftor (VX-770), is a drug directed to type III mutations in homozygote patients for Phe508del.

Given that lumacaftor helps the movement of Phe508del CFTR to the cell surface and the ivacaftor increases the opening time and the Cl- conductance through the epithelial cell, the treatment can be possible with a combination of the two drugs.

Another alternative compound is VX-661 that is being studied. Its efficiency is being evaluated by itself and together with ivacaftor.