Asymmetric turnover dynamics of Nav1.6 voltage-gated sodium channels at the axon initial segment
- 1Laboratory of Integrative Physiology, Department of Physiology, Graduate School of Medicine, The University of Osaka, Suita, Osaka 565-0871, Japan
Abstract
Nav1.6 voltage-gated sodium channels are critical for shaping action potentials, and their precise localization at the axon initial segment (AIS) is essential for neuronal excitability. However, the turnover mechanisms that maintain this spatial pattern remain unclear. Here, we present a genetically engineered mouse in which endogenous Nav1.6 carries a Cre-switchable fluorescent tag, enabling us to simultaneously trace the turnover of pre-existing and newly synthesized Nav1.6 without perturbing AIS structure. Using this system, we determine the physiological lifetimes of Nav1.6 at the AIS in vivo and in vitro, and further uncover the spatially asymmetric turnover dynamics, with the proximal and distal AIS organizing a source-to-sink gradient. Based on the quantified parameters, computational modeling clarifies that this asymmetry promotes efficient clearance of older molecules, thereby supporting AIS quality control. Collectively, these findings provide a technical and conceptual foundation for understanding how molecular turnover contributes to AIS homeostasis.
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BibTeX
@misc{yoshioka2026asymmetric,
title = {{Asymmetric turnover dynamics of Nav1.6 voltage-gated sodium channels at the axon initial segment}},
author = {D. Yoshioka and K. Yamamoto and L. Huang and M. Abe and K. Sakimura and T. Kawai and Y. Okochi and Y. Okamura},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.10.747750},
url = {https://www.biorxiv.org/content/10.64898/2026.09.10.747750v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Asymmetric turnover dynamics of Nav1.6 voltage-gated sodium channels at the axon initial segment
AU - D. Yoshioka
AU - K. Yamamoto
AU - L. Huang
AU - M. Abe
AU - K. Sakimura
AU - T. Kawai
AU - Y. Okochi
AU - Y. Okamura
PY - 2026
DA - 2026/09/10
PB - bioRxiv
DO - 10.64898/2026.09.10.747750
UR - https://www.biorxiv.org/content/10.64898/2026.09.10.747750v1
AB - Nav1.6 voltage-gated sodium channels are critical for shaping action potentials, and their precise localization at the axon initial segment (AIS) is essential for neuronal excitability. However, the turnover mechanisms that maintain this spatial pattern remain unclear. Here, we present a genetically engineered mouse in which endogenous Nav1.6 carries a Cre-switchable fluorescent tag, enabling us to simultaneously trace the turnover of pre-existing and newly synthesized Nav1.6 without perturbing AIS structure. Using this system, we determine the physiological lifetimes of Nav1.6 at the AIS in vivo and in vitro, and further uncover the spatially asymmetric turnover dynamics, with the proximal and distal AIS organizing a source-to-sink gradient. Based on the quantified parameters, computational modeling clarifies that this asymmetry promotes efficient clearance of older molecules, thereby supporting AIS quality control. Collectively, these findings provide a technical and conceptual foundation for understanding how molecular turnover contributes to AIS homeostasis.
ER -