Science Topics – 186
KCNQ2/3, a major voltage-gated potassium channel at the axon initial segment (AIS), plays a crucial role in controlling neuronal excitability. Since neurons are highly polarized cells, the impact of KCNQ2/3 on neuronal activity is regulated not only by the functionality of channels but also by their localization at the axon initial segment (AIS), the site of action potential initiation. While the functionality of KCNQ2/3 is regulated by conformational changes from voltage sensing, the AIS localization of KCNQ2/3 is regulated by ankyrinG (ankG), the AIS master organizer. However, the potential coupling between the mechanisms governing channel functionality and trafficking remains unresolved. Here, we combine genetic engineering of channel functionality with advanced imaging techniques of channel trafficking to uncover a coupling of KCNQ2/3 functionality to trafficking. Single-molecule imaging reveals that reduced KCNQ3 functionality alters the entire trafficking pathway, including exo/endocytosis and lateral diffusion, reducing AIS localization of KCNQ2/3. Furthermore, we develop a live-cell assay to quantify the interactions between full-length KCNQ3 and ankG, demonstrating that the active conformation of KCNQ3 is essential for the stable ankG binding. Our findings establish a mechanistic basis for the integration of KCNQ2/3 gating and trafficking in regulating neuronal excitability. This unified framework for the KCNQ2/3 gating and trafficking provides insights into AIS quality control and KCNQ2/3-related epilepsy.
Yoshioka D, Okamura Y. Coupling of Functionality to Trafficking of KCNQ2/3 Potassium Channels at the Axon Initial Segment. Proceedings of the National Academy of Sciences of the United States of America (PNAS): 123(10), 2026.
＜Figure Legends＞
Figure 1. Coupling of channel functionality to AIS localization of KCNQ2/3.
We demonstrated that while functional KCNQ2/3 channels (left) are strongly enriched at the AIS, the functionally impaired KCNQ2/3 mutant (right) shows a significant reduction in AIS localization efficiency. The arrow indicates the position of AIS. Scale bar, 20 µm.
Department of Physiology, Graduate School of Medicine, The University of Osaka, Japan