An imbalance of salt and water in patients with cystic fibrosis makes their lungs clog up with sticky mucus that is prone to infection. The cause of the offending imbalance is a well-known genetic error, one that blocks the molecular expressway for tiny chloride ions to move across the surface of the lungs.
But how does that same gene mutation upset a parallel roadway controlling the flow of the other component of salt, sodium ions? Now, researchers at the University of North Carolina at Chapel Hill School of Medicine have found the answer, demonstrating that the gene mutated in cystic fibrosis not only controls traffic on the chloride highway, but also keeps the sodium highway from being overused.
The finding suggests that the infamous mutation – in a gene called CFTR – is a double whammy, affecting the flow of two different ions that are important to keep the mucus on the surfaces of the airways hydrated. Clarifying this link between the genetic defect and the thick sticky mucus in cystic fibrosis lungs could help researchers develop better therapies.
“It is very important to slow down this sodium channel when it is overactive before it leads to dehydration of the mucus in patient airways,” said Martina Gentzsch, PhD, assistant professor of cell and developmental biology at UNC and lead author of a study published Oct. 15 in the Journal of Biological Chemistry. “If we can understand the mechanism of how CFTR does that, it might give us a new approach to treat the disease.”
Cystic fibrosis is one of the most common genetic diseases in Caucasians, affecting approximately 1 in 3500 births in the United States. It is caused by a defect in the gene that codes for a protein called cystic fibrosis transmembrane conductance regulator or CFTR. Cystic fibrosis patients with the most severe disease have very little of the CFTR protein, and this affects the way chloride ions move across many tissues in the body. A number of scientists have hypothesized that CFTR also controls the movement of other ions, such as through the epithelial sodium channel or ENaC.
This channel has been shown to be overactive in transporting sodium ions in the airways of cystic fibrosis patients, so Gentzsch and her colleagues set out to determine why. First, they looked at the effects of the CFTR gene on the sodium channel in xenopus oocytes, commonly known as frog eggs. They found that when the CFTR gene was intact, the sodium channel was kept in check.
The researchers followed up with a number of biochemical and electrophysiological experiments and showed that the chloride channel and the sodium channels interact. Gentzsch and her colleagues also confirmed their results in human primary airway epithelial cells from healthy volunteers and patients with cystic fibrosis, showing that the sodium channel was in fact more active when there was no functional CFTR.
Now that they know that the chloride channel can actually influence the function of the sodium channel, Gentzsch is trying to find out how.
“We don’t know if it is doing this by basically acting like a roadblock, physically interfering with the proteases that activate ENaC, or if it is doing it by some indirect means,” said Gentzsch. “That is what we are investigating at the moment, so there are a lot of more questions to be answered.”
The research was funded by the National Institutes of Health and performed at the Cystic Fibrosis/Pulmonary Research and Treatment Center at the University of North Carolina, which also receives funding from the Cystic Fibrosis Foundation. Study co-authors include Richard C. Boucher, MD, director of the Cystic Fibrosis/Pulmonary Research and Treatment Center; and M. Jackson Stutts, PhD, professor of medicine.
Les Lang | EurekAlert!
World’s Largest Study on Allergic Rhinitis Reveals new Risk Genes
17.07.2018 | Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt
Plant mothers talk to their embryos via the hormone auxin
17.07.2018 | Institute of Science and Technology Austria
For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.
To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...
For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.
Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...
Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.
A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...
Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.
"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....
Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.
Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...
13.07.2018 | Event News
12.07.2018 | Event News
03.07.2018 | Event News
17.07.2018 | Life Sciences
17.07.2018 | Information Technology
17.07.2018 | Power and Electrical Engineering