Sodium channel Nav1.8 underlies TTX-resistant axonal action potential conduction in somatosensory C-fibers of distal cutaneous nerves

Amanda H. Klein, Alina Vyshnevska, Timothy V. Hartke, Roberto De Col, Joseph L Mankowski, Brian Turnquist, Frank Bosmans, Peter W. Reeh, Martin Schmelz, Richard W. Carr, Matthias Ringkamp

Research output: Contribution to journalArticle

Abstract

Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1–NaV1.4, NaV1.6–NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys (Macacanemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and NaV1.9-/- mice. In nerves from NaV1.8-/- mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.

Original languageEnglish (US)
Pages (from-to)5204-5214
Number of pages11
JournalJournal of Neuroscience
Volume37
Issue number20
DOIs
StatePublished - May 17 2017

Fingerprint

Unmyelinated Nerve Fibers
Sodium Channels
Tetrodotoxin
Action Potentials
Skin
Axons
Protein Isoforms
Spinal Nerve Roots
Peripheral Nerves
Macaca nemestrina
Voltage-Gated Sodium Channels
Afferent Neurons
Presynaptic Terminals
Primates
Haplorhini
Mammals
Pain

Keywords

  • Nociceptor
  • Nonhuman primate
  • Pain
  • Sodium channels

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Sodium channel Nav1.8 underlies TTX-resistant axonal action potential conduction in somatosensory C-fibers of distal cutaneous nerves. / Klein, Amanda H.; Vyshnevska, Alina; Hartke, Timothy V.; De Col, Roberto; Mankowski, Joseph L; Turnquist, Brian; Bosmans, Frank; Reeh, Peter W.; Schmelz, Martin; Carr, Richard W.; Ringkamp, Matthias.

In: Journal of Neuroscience, Vol. 37, No. 20, 17.05.2017, p. 5204-5214.

Research output: Contribution to journalArticle

Klein, Amanda H. ; Vyshnevska, Alina ; Hartke, Timothy V. ; De Col, Roberto ; Mankowski, Joseph L ; Turnquist, Brian ; Bosmans, Frank ; Reeh, Peter W. ; Schmelz, Martin ; Carr, Richard W. ; Ringkamp, Matthias. / Sodium channel Nav1.8 underlies TTX-resistant axonal action potential conduction in somatosensory C-fibers of distal cutaneous nerves. In: Journal of Neuroscience. 2017 ; Vol. 37, No. 20. pp. 5204-5214.
@article{e92bbbbc5f1f4edc8e445111568d9a95,
title = "Sodium channel Nav1.8 underlies TTX-resistant axonal action potential conduction in somatosensory C-fibers of distal cutaneous nerves",
abstract = "Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1–NaV1.4, NaV1.6–NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys (Macacanemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16{\%} of the baseline. In contrast, >30{\%} of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and NaV1.9-/- mice. In nerves from NaV1.8-/- mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.",
keywords = "Nociceptor, Nonhuman primate, Pain, Sodium channels",
author = "Klein, {Amanda H.} and Alina Vyshnevska and Hartke, {Timothy V.} and {De Col}, Roberto and Mankowski, {Joseph L} and Brian Turnquist and Frank Bosmans and Reeh, {Peter W.} and Martin Schmelz and Carr, {Richard W.} and Matthias Ringkamp",
year = "2017",
month = "5",
day = "17",
doi = "10.1523/JNEUROSCI.3799-16.2017",
language = "English (US)",
volume = "37",
pages = "5204--5214",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "20",

}

TY - JOUR

T1 - Sodium channel Nav1.8 underlies TTX-resistant axonal action potential conduction in somatosensory C-fibers of distal cutaneous nerves

AU - Klein, Amanda H.

AU - Vyshnevska, Alina

AU - Hartke, Timothy V.

AU - De Col, Roberto

AU - Mankowski, Joseph L

AU - Turnquist, Brian

AU - Bosmans, Frank

AU - Reeh, Peter W.

AU - Schmelz, Martin

AU - Carr, Richard W.

AU - Ringkamp, Matthias

PY - 2017/5/17

Y1 - 2017/5/17

N2 - Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1–NaV1.4, NaV1.6–NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys (Macacanemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and NaV1.9-/- mice. In nerves from NaV1.8-/- mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.

AB - Voltage-gated sodium (NaV) channels are responsible for the initiation and conduction of action potentials within primary afferents. The nine NaV channel isoforms recognized in mammals are often functionally divided into tetrodotoxin (TTX)-sensitive (TTX-s) channels (NaV1.1–NaV1.4, NaV1.6–NaV1.7) that are blocked by nanomolar concentrations and TTX-resistant (TTX-r) channels (NaV1.8 and NaV1.9) inhibited by millimolar concentrations, with NaV1.5 having an intermediate toxin sensitivity. For small-diameter primary afferent neurons, it is unclear to what extent different NaV channel isoforms are distributed along the peripheral and central branches of their bifurcated axons. To determine the relative contribution of TTX-s and TTX-r channels to action potential conduction in different axonal compartments, we investigated the effects of TTX on C-fiber-mediated compound action potentials (C-CAPs) of proximal and distal peripheral nerve segments and dorsal roots from mice and pigtail monkeys (Macacanemestrina). In the dorsal roots and proximal peripheral nerves of mice and nonhuman primates, TTX reduced the C-CAP amplitude to 16% of the baseline. In contrast, >30% of the C-CAP was resistant to TTX in distal peripheral branches of monkeys and WT and NaV1.9-/- mice. In nerves from NaV1.8-/- mice, TTX-r C-CAPs could not be detected. These data indicate that NaV1.8 is the primary isoform underlying TTX-r conduction in distal axons of somatosensory C-fibers. Furthermore, there is a differential spatial distribution of NaV1.8 within C-fiber axons, being functionally more prominent in the most distal axons and terminal regions. The enrichment of NaV1.8 in distal axons may provide a useful target in the treatment of pain of peripheral origin.

KW - Nociceptor

KW - Nonhuman primate

KW - Pain

KW - Sodium channels

UR - http://www.scopus.com/inward/record.url?scp=85019954998&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019954998&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3799-16.2017

DO - 10.1523/JNEUROSCI.3799-16.2017

M3 - Article

VL - 37

SP - 5204

EP - 5214

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 20

ER -