Researchers from The University of Osaka find that potassium KCNQ2/3 channels, which are important for suppressing brain cell excitability, require normal functionality to ensure their proper cellular localization

Osaka, Japan – Potassium KCNQ2/3 channels are crucial for suppressing the excitability of brain cells, or neurons. When these channels don’t work properly, they can cause specific types of epilepsy like benign familial neonatal convulsions and early infantile epileptic encephalopathy.

In a study published recently in PNAS, Japanese researchers have revealed the relationship between KCNQ2/3 channel functionality (i.e., how well they work to control electrical signals in neurons) and localization (i.e., where they are found inside a cell), with important implications for the treatment of these epileptic disorders.

For KCNQ2/3 channels to work properly in the brain, they must have full functionality and be located in the correct cellular region – specifically the axon initial segment (AIS), the site in neurons where electric signals are first triggered, controlling nerve cell activity. This led the research team to wonder: does the functionality of KCNQ2/3 channels affect their cellular localization, or are the two not linked at all?

To investigate this potential association, the research team first genetically engineered the functionality of the channels, and then used channel trafficking imaging to visualize whether the channels were taken to their location in the AIS. In this way, they demonstrated that KCNQ2/3 functionality was indeed linked to its trafficking to the correct cellular localization. What’s more, when they used single-molecule imaging, they could see that reduced KCNQ3 functionality actually reduced the AIS localization of KCNQ2/3 by altering the entire trafficking pathway.

“Because we already knew that the localization of KCNQ2/3 to the AIS is regulated by a protein known as ankyrinG, or ankG, we next decided to explore the interactions between full-length KCNQ3 and ankG,” explains lead author of the study Daisuke Yoshioka. “We found that the active conformation of KCNQ3 was essential for its stable binding to ankG, further confirming that functional KCNQ2/3 is needed to ensure its proper accumulation at the AIS.”

Together, these findings highlight the mechanisms underlying the important link between KCNQ2/3 functionality and localization, and provide clues about how their alterations might affect neuronal excitability.

“Now that we know that KCNQ2/3 functionality is closely linked to its localization at the AIS, we have a more concrete target for studying disorders involving altered KCNQ2/3 channels,” says Yasushi Okamura, senior author of the study. “Keeping these potassium channels functioning properly may also be important for ensuring they reach the proper location in brain cells.”

Given that KCNQ2/3‑related neurological disorders, including epilepsy, remain relatively poorly understood and can be difficult to treat, these findings have important implications. They may contribute to the development of new therapeutic strategies that improve the quality of life for young patients and their families.

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The article, “Coupling of Functionality to Trafficking of KCNQ2/3 Potassium Channels at the Axon Initial Segment,” was published in PNAS at DOI: https://doi.org/10.1073/pnas.2527749123


About The University of Osaka
The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en