Chloride-channel in muscle cells provides new insights for muscle diseases

April 30, 2019

Small molecules such as hormones and ions are constantly transported in and out from our cells. This regulates what the cells do in our bodies. That is also why many researchers try to understand what controls the different channels in our cells. They have now greatly improved this understanding for muscle cells.

In a new study, an international and inter-disciplinary team involving researchers from the Faculty of Science and the Faculty of Health and Medical Sciences at the University of Copenhagen have mapped the structure of a channel that transports chloride into our muscle cells. Detailed structures of the chloride channel will provide vital information in the quest to fully understand its regulation and thereby optimize development of better treatments of important diseases such as ALS, SMA or Myasthenia gravis.

"This channel in the muscle cells may be essential for the group of illnesses we call neuromuscular diseases. That applies, for instance, to ALS, which many people might know from the late physicist Stephen Hawking. Others have discovered that blocking the channel can alleviate the symptoms of ALS. Our new findings will spark on-going development efforts to block the channel," says Pontus Gourdon, Associate Professor at Department of Biomedical Sciences.

Cryo-electron microscopy

The researchers have investigated proteins that exist in the cell membranes of human cells using a state-of-the-art so-called cryo-electron microscope. It uses rays of electrons to visualise the 3D-structures of different biological molecules.

In this instance, the researchers have taken what one might call a 3D-photography of this chloride-channel in muscle cells. Visualisations like these pave the way to more efficient drug development because they allow a more rational effort on medical compounds that can bind to that specific 3D-structure.

NMD Pharma

Previous work from Aarhus University has revealed that the chloride-channel is critical for maintenance of skeletal muscle function during physical activity, and this led to the formation of NMD Pharma, a pharmaceutical company that is pursuing new treatments for neuromuscular disorders by targeting the chloride channel.

The researchers have now initiated a collaboration with NMD Pharma that will use the new knowledge for drug development. A postdoc from the research group at the university will collaborate closely with scientists of NMD Pharma to help make the most of the new findings.

Value in society

The new post-doc employment is part of the public-private partnership called BRIDGE between university and industry. The goal is to make sure that knowledge from research results makes it beyond scientific publications and has a positive impact in society. The program is supported by the Novo Nordisk Foundation.

"We are extremely proud of the fact that our research might lead to real impact in society through this collaboration. And also of the fact that the industry can see the values of our findings," says Pontus Gourdon.

He emphasizes that drug development can take a long time and that approval of new drugs is no quick process either.

The new results are especially relevant for neuromuscular diseases such as Thomsen's disease.

It is a heritable disease named after the Danish physician Asmus Julius Thomas Thomsen who described the disease in 1876. Many in his family, including himself, suffered from the disease.
The study is funded by The Lundbeck Foundation, Knut and Alice Wallenbergs Foundation, The Carlsberg Foundation and the Novo Nordisk Foundation.

The new study is published in the scientific journal PLOS Biology. Read the scientific article: "Structure of the human ClC-1 chloride channel".

University of Copenhagen The Faculty of Health and Medical Sciences

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