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Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels.

Publication ,  Journal Article
Liu, H; Wang, H-G; Pitt, GS; Liu, ZJ
Published in: J Neurosci
June 6, 2022

Brain enriched voltage-gated sodium channel (VGSC) Nav1.2 and Nav1.6 are critical for electrical signaling in the central nervous system. Previous studies have extensively characterized cell-type specific expression and electrophysiological properties of these two VGSCs and how their differences contribute to fine-tuning of neuronal excitability. However, due to lack of reliable labeling and imaging methods, the sub-cellular localization and dynamics of these homologous Nav1.2 and Nav1.6 channels remain understudied. To overcome this challenge, we combined genome editing, super-resolution and live-cell single molecule imaging to probe subcellular composition, relative abundances and trafficking dynamics of Nav1.2 and Nav1.6 in cultured mouse and rat neurons and in male and female mouse brain. We discovered a previously uncharacterized trafficking pathway that targets Nav1.2 to the distal axon of unmyelinated neurons. This pathway utilizes distinct signals residing in the intracellular loop 1 (ICL1) between transmembrane domain I and II to suppress the retention of Nav1.2 in the axon initial segment (AIS) and facilitate its membrane loading at the distal axon. As mouse pyramidal neurons undergo myelination, Nav1.2 is gradually excluded from the distal axon as Nav1.6 becomes the dominant VGSC in the axon initial segment and nodes of Ranvier. In addition, we revealed exquisite developmental regulation of Nav1.2 and Nav1.6 localizations in the axon initial segment and dendrites, clarifying the molecular identity of sodium channels in these subcellular compartments. Together, these results unveiled compartment-specific localizations and trafficking mechanisms for VGSCs, which could be regulated separately to modulate membrane excitability in the brain.SIGNIFICANCE STATEMENTDirect observation of endogenous voltage-gated sodium channels reveals a previously uncharacterized distal axon targeting mechanism and the molecular identity of sodium channels in distinct subcellular compartments.

Duke Scholars

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

June 6, 2022

Volume

42

Issue

28

Start / End Page

5482 / 5498

Location

United States

Related Subject Headings

  • Neurology & Neurosurgery
  • 3209 Neurosciences
  • 17 Psychology and Cognitive Sciences
  • 11 Medical and Health Sciences
 

Citation

APA
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ICMJE
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Liu, H., Wang, H.-G., Pitt, G. S., & Liu, Z. J. (2022). Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels. J Neurosci, 42(28), 5482–5498. https://doi.org/10.1523/JNEUROSCI.0086-22.2022
Liu, Hui, Hong-Gang Wang, Geoffrey S. Pitt, and Zhe J. Liu. “Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels.J Neurosci 42, no. 28 (June 6, 2022): 5482–98. https://doi.org/10.1523/JNEUROSCI.0086-22.2022.
Liu H, Wang H-G, Pitt GS, Liu ZJ. Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels. J Neurosci. 2022 Jun 6;42(28):5482–98.
Liu, Hui, et al. “Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels.J Neurosci, vol. 42, no. 28, June 2022, pp. 5482–98. Pubmed, doi:10.1523/JNEUROSCI.0086-22.2022.
Liu H, Wang H-G, Pitt GS, Liu ZJ. Direct Observation of Compartment-Specific Localization and Dynamics of Voltage-Gated Sodium Channels. J Neurosci. 2022 Jun 6;42(28):5482–5498.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

June 6, 2022

Volume

42

Issue

28

Start / End Page

5482 / 5498

Location

United States

Related Subject Headings

  • Neurology & Neurosurgery
  • 3209 Neurosciences
  • 17 Psychology and Cognitive Sciences
  • 11 Medical and Health Sciences