CFTR correctors found to boost potassium flow in CF lung cells
Potassium flow via BKCa channel known to support hydration of lung surfaces
CFTR correctors, such as elexacaftor, a component of the cystic fibrosis (CF) therapy Trikafta, may improve lung function through enhanced potassium flow via a protein channel called BKCa, a study has found.
Potassium flow via BKCa is known to support the hydration of lung surfaces, similar to CFTR, which is the protein that’s defective or missing in people with CF.
However, BKCa activation also triggers the widening of blood vessels and changes in nerve cell activity, which may explain certain side effects associated with CFTR correctors.
“We raise the possibilities that … CFTR correctors gain additional clinical benefit by activation of BKCa in the lung, yet may lead to adverse events through BKCa activation, elsewhere,” researchers noted.
The discovery was reported in the study “Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator (CFTR) correctors VX-445 and VX-121,” published in The Journal of Clinical Investigation.
Function, production of CFTR protein affected by CF genetic mutations
CF is caused by genetic mutations that affect the function and production of the CFTR protein, which serves as a channel to transport chloride in and out of cells. Chloride flow helps maintain the water content of mucus, which coats and protects the surface of tissues. Without functional CFTR, the mucus becomes thick and sticky, particularly in the lungs and intestines, leading to CF symptoms.
CFTR modulators are a class of therapies that repair the defects in the production and/or function of the mutated CFTR protein. Among them, CFTR correctors restore the protein’s folding and trafficking to the cell membrane, while CFTR potentiators improve chloride flow at the cell membrane.
In addition to chloride, the movement of potassium, via a channel called BKCa, is also critical for maintaining the water content on lung surfaces. In fact, the CF-related release of pro-inflammatory signaling proteins triggers a reduction in BKCa production, further contributing to a loss of water balance.
Given BKCa’s role in modulating surface water content, a team led by researchers at the University of Pittsburgh, in Pennsylvania, measured the effect of two CFTR correctors on potassium secretion from human bronchial epithelial cells (HBEs), which line the airways.
The CFTR corrector called elexacaftor, a component of the triple combination therapy Trikafta, induced potassium secretion in HBEs that were healthy or carried the most common CF-causing mutation called F508del. Potassium flow was inhibited by a small molecule (paxilline) that blocked BKCa.
A second corrector, vanzacaftor (VX-121), part of another triple combo treatment that is awaiting regulatory decisions in the U.S. and Europe, also stimulated a large increase in paxilline-sensitive potassium secretion.
However, the other two components of Trikafta, tezacaftor (a corrector) and ivacaftor (a potentiator), had no effect on potassium flow in HBEs. Tezacaftor is a C1-type corrector that targets the early folding of mutant CFTR, while elexacaftor and VX-121 are both C2-type correctors that work via different mechanisms and can enhance the benefits of a C1 corrector.
Elexacaftor, vanzacaftor increase potassium secretion via BKCa protein
By measuring the electrical current produced by the flow of positively charged potassium ions, the researchers confirmed that elexacaftor and vanzacaftor increased potassium secretion via the BKCa protein.
Because BKCa is widely produced throughout the body, the impact of CFTR correctors on other tissues was explored.
Both elexacaftor and vanzacaftor were found to relax preconstricted mouse arteries in a dose-dependent manner. They also reduced the electrical activity of nerve cells from different regions of rat brains. These effects were seen at doses within the range of those found in the blood and tissues of CF patients.
The effect of CFTR correctors on blood vessels via BKCa may explain treatment-related side effects observed in clinical trials, such as high blood pressure, which has led to treatment discontinuations, according to the researchers. Moreover, their impact on nerve cell activity may lead to changes in mental state, such as symptoms of “mental fogginess” reported with Trikafta.
“While C2 corrector-dependent potentiation of BKCa may be of benefit in airway epithelia, the cross-reactivity with BKCa in other tissues may contribute to the adverse events … reported by CF patients upon initiation of [Trikafta],” the researchers wrote.
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