Potassium channels functionality is coupled to trafficking!
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, 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. “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 the 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.
https://www.pnas.org/doi/10.1073/pnas.2527749123
