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Featured ArticleResearch Articles, Cellular/Molecular

Depolarizing NaV and Hyperpolarizing KV Channels Are Co-Trafficked in Sensory Neurons

Grant P. Higerd-Rusli, Matthew Alsaloum, Sidharth Tyagi, Nivedita Sarveswaran, Mark Estacion, Elizabeth J. Akin, Fadia B. Dib-Hajj, Shujun Liu, Daniel Sosniak, Peng Zhao, Sulayman D. Dib-Hajj and Stephen G. Waxman
Journal of Neuroscience 15 June 2022, 42 (24) 4794-4811; DOI: https://doi.org/10.1523/JNEUROSCI.0058-22.2022
Grant P. Higerd-Rusli
1MD/PhD Program
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Matthew Alsaloum
1MD/PhD Program
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Sidharth Tyagi
1MD/PhD Program
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Nivedita Sarveswaran
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Mark Estacion
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Elizabeth J. Akin
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Fadia B. Dib-Hajj
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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  • ORCID record for Fadia B. Dib-Hajj
Shujun Liu
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Daniel Sosniak
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Peng Zhao
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Sulayman D. Dib-Hajj
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Stephen G. Waxman
2Center for Neuroscience and Regeneration Research and
3Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06510
4Rehabilitation Research Center, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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Abstract

Neuronal excitability relies on coordinated action of functionally distinction channels. Voltage-gated sodium (NaV) and potassium (KV) channels have distinct but complementary roles in firing action potentials: NaV channels provide depolarizing current while KV channels provide hyperpolarizing current. Mutations and dysfunction of multiple NaV and KV channels underlie disorders of excitability, including pain and epilepsy. Modulating ion channel trafficking may offer a potential therapeutic strategy for these diseases. A fundamental question, however, is whether these channels with distinct functional roles are transported independently or packaged together in the same vesicles in sensory axons. We have used Optical Pulse-Chase Axonal Long-distance imaging to investigate trafficking of NaV and KV channels and other axonal proteins from distinct functional classes in live rodent sensory neurons (from male and female rats). We show that, similar to NaV1.7 channels, NaV1.8 and KV7.2 channels are transported in Rab6a-positive vesicles, and that each of the NaV channel isoforms expressed in healthy, mature sensory neurons (NaV1.6, NaV1.7, NaV1.8, and NaV1.9) is cotransported in the same vesicles. Further, we show that multiple axonal membrane proteins with different physiological functions (NaV1.7, KV7.2, and TNFR1) are cotransported in the same vesicles. However, vesicular packaging of axonal membrane proteins is not indiscriminate, since another axonal membrane protein (NCX2) is transported in separate vesicles. These results shed new light on the development and organization of sensory neuron membranes, revealing complex sorting of axonal proteins with diverse physiological functions into specific transport vesicles.

SIGNIFICANCE STATEMENT Normal neuronal excitability is dependent on precise regulation of membrane proteins, including NaV and KV channels, and imbalance in the level of these channels at the plasma membrane could lead to excitability disorders. Ion channel trafficking could potentially be targeted therapeutically, which would require better understanding of the mechanisms underlying trafficking of functionally diverse channels. Optical Pulse-chase Axonal Long-distance imaging in live neurons permitted examination of the specificity of ion channel trafficking, revealing co-packaging of axonal proteins with opposing physiological functions into the same transport vesicles. This suggests that additional trafficking mechanisms are necessary to regulate levels of surface channels, and reveals an important consideration for therapeutic strategies that target ion channel trafficking for the treatment of excitability disorders.

  • axonal trafficking
  • ion channels
  • live microscopy
  • sensory neurons

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The Journal of Neuroscience: 42 (24)
Journal of Neuroscience
Vol. 42, Issue 24
15 Jun 2022
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Depolarizing NaV and Hyperpolarizing KV Channels Are Co-Trafficked in Sensory Neurons
Grant P. Higerd-Rusli, Matthew Alsaloum, Sidharth Tyagi, Nivedita Sarveswaran, Mark Estacion, Elizabeth J. Akin, Fadia B. Dib-Hajj, Shujun Liu, Daniel Sosniak, Peng Zhao, Sulayman D. Dib-Hajj, Stephen G. Waxman
Journal of Neuroscience 15 June 2022, 42 (24) 4794-4811; DOI: 10.1523/JNEUROSCI.0058-22.2022

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Depolarizing NaV and Hyperpolarizing KV Channels Are Co-Trafficked in Sensory Neurons
Grant P. Higerd-Rusli, Matthew Alsaloum, Sidharth Tyagi, Nivedita Sarveswaran, Mark Estacion, Elizabeth J. Akin, Fadia B. Dib-Hajj, Shujun Liu, Daniel Sosniak, Peng Zhao, Sulayman D. Dib-Hajj, Stephen G. Waxman
Journal of Neuroscience 15 June 2022, 42 (24) 4794-4811; DOI: 10.1523/JNEUROSCI.0058-22.2022
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Keywords

  • axonal trafficking
  • ion channels
  • live microscopy
  • sensory neurons

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