In solving a 20-year mystery about the role of a protein associated with mucus production, researchers provide new insights that may lead to new treatments for asthma, chronic obstructive pulmonary disease, cystic fibrosis and other diseases.
The researchers, from Washington University School of Medicine in St. Louis (WUSTL), MO, report their findings in the journal eLife.
Thomas J. Brett, senior study author and assistant professor of medicine at WUSTL, says:
“The new study lays the groundwork for developing treatments for diseases such as asthma, COPD, cystic fibrosis and even certain cancers.”
In diseases such as asthma and chronic obstructive pulmonary disease (COPD), the body produces too much mucus, making breathing difficult.
In cystic fibrosis, the mucus that is produced is too thick and clogs up the lungs and digestive tract.
The significance of the new study lies in revelations about ion channels – special proteins that make pores in the cell membrane and help regulate the flow of charged particles in and out of the cell.
Ion channels allow cells to send and receive electrical signals and perform roles essential to health, such as secrete substances like mucus, control heart rhythm and support brain function.
For example, the flow of chloride ions in and out of cells helps to control the production of mucus – a protective lining in our windpipe and other airways. Mucus – which is made of glycoproteins and water – traps pollution and foreign particles before they can do harm to the lungs.
However, with diseases like cystic fibrosis and asthma, too much mucus that is too thick is produced, which makes breathing difficult and raises risk of infection.
About 20 years ago, scientists identified a protein called CLCA1, which when found in high levels in cells lining the airway, has long been linked to overproduction of mucus. For a long time, it was thought CLCA1 was a chloride ion channel because members of the CLCA protein family appeared to be moving chloride ions in and out of cells.
Eventually, as more clues were found, scientists decided CLCA proteins were not channels but triggers; they activated channels to allow chloride ions to pass through cell membranes. However, it was not clear which channels the CLCA proteins were triggering and how. Prof. Brett notes:
“When cells express CLCA1, they produce chloride currents. But as we became better at understanding the three-dimensional structures of proteins, researchers in the field started to realize that CLCA proteins couldn’t be channels. So the question arose, how do they activate these currents if they’re not channels?”
Prof. Brett and his team found that when CLCA1 is released from human cells, it causes the release of chloride ions when the channel detects the presence of calcium ions.
The team also noticed that the movement of chloride ions triggered by CLCA1 looks very similar to the way chloride ions pass through a channel known as TMEM16A, so they decided to investigate whether these two proteins interact.
TMEM16A – which was only discovered only 7 years ago in mammals – is found in abundance in cells lining the airway. There is evidence that too much TMEM16A – like too much CLCA1 – is associated with overproduction of mucus in respiratory diseases like asthma and COPD.
With his colleagues, Prof. Brett showed that CLCA1 triggers TMEM16A, and increased expression of CLCA1 increases the number of TMEM16A channels present in nearby cells. He explains:
“We don’t think that CLCA1 actually opens the channel. In fact, the channel can function without CLCA1. We think it simply keeps the channel on the surface of the cells for a longer period of time.”
He says the reason there is more current is because there are more channels open – more holes for the ions to pass through, and adds:
“This is a unique finding. We don’t know of any other examples of this type of interaction between a protein and a channel.”
The findings have wider implications. If other members of the families these proteins belong to also interact with each other, then this could shed light on a diverse range of disorders including cancer and cardiovascular diseases.
For instance, TMEM16 channels and CLCA proteins are linked to certain types of cancer, including breast tumors that spread to the lung. They have also been implicated in cardiovascular diseases, such as irregular heart rhythm disorders and heart failure.
The team is continuing to study the interaction between the protein and the channel, and how increasing or decreasing their expression may affect ion flows and impact airway diseases.
The study was funded by the National Institutes of Health (NIH), the American Lung Association, the Center for the Investigation of Membrane Excitability Diseases and the American Heart Association.
Meanwhile, Medical News Today recently learned about a new study published in The BMJ that found participants who followed a healthy diet were a third less likely to develop COPD, compared with those who did not. The researchers defined a healthy diet as one high in vegetables, whole grains, polyunsaturated fats, nuts and omega-3 fatty acids, and low in red and processed meats, refined grains and sugary drinks.