With philanthropic funding, U-M researcher will probe therapeutic potential of a previously overlooked protein
On the surface of almost every cell in your body, molecules called ion channels serve as gatekeepers, controlling the flow of different ions in and out of the cell to regulate the cell’s electrochemical state. A structural biologist at the University of Michigan Life Sciences Institute now hopes to unlock the secrets — and therapeutic potential — of one poorly understood subtype of these channels, with support from the Klatskin-Sutker Discovery Fund.
Potassium ion channels are one of the most common, and well-studied, types of ion channels. Their widespread role in coordinating cellular processes has made them a prime target for treating disorders from multiple sclerosis to heart disease. But one small branch of this family, called two-pore-domain K+ channels (K2P channels), is unaffected by the typical channel blocking drugs currently available the market.
“The overall architecture of K2P channels, the way the proteins fold, is very different from other potassium ion channels. So existing blockers cannot bind to them the same way,” explains Qianqian Ma, Ph.D., a research investigator in the lab of Shyamal Mosalaganti, Ph.D., and the recipient of this year’s Klatskin-Sutker award. “And I think people are just starting to realize how important this subfamily of potassium channels is.”
Recent research indicates that one member of this subfamily is involved in inflammation, particularly related to lung disease, while other members are implicated in heart disease and neurodegenerative disorders. To design drugs that block K2P channels, though, scientists need a clearer understanding of how their structure affects their activity.
Ma will use the new funding to identify compounds that more effectively bind to and block one member of the K2P channel family, by screening tens of thousands of chemical compounds in the LSI’s Center for Chemical Genomics. She then plans to use advanced microscopy techniques to reveal a clearer picture of the K2P channel bound to candidate compounds.
It is essential that scientists have the opportunity to pursue these types of emergent, innovative projects, because these are precisely the projects that can ultimately transform our approaches to human health and disease.
Ultimately, Ma wants to determine exactly where and how a drug binds to the channel. With that knowledge, she and her colleagues can better understand how the protein is regulated by the drug so they can design more specific versions for other members of this subfamily.
“Screening the small molecule drugs is kind of high risk, because right now there are no known blockers with high affinity for this specific type of potassium channel; so we do not necessarily have a defined starting point” Ma says. “But it’s also high reward, because if we find some potential candidates, it could provide a blueprint for developing new anti-inflammatory drugs.”
The Klatskin-Sutker Discovery Fund was established by the Klatskin and Sutker families to kickstart early-stage projects that have the potential to impact human health but are not yet ready for more traditional funding programs such as large governmental grants.
“It is essential that scientists have the opportunity to pursue these types of emergent, innovative projects, because these are precisely the projects that can ultimately transform our approaches to human health and disease,” says Deborah Klatskin.