Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase

Ellen K. Wittmack, Anthony M. Rush, Andy Hudmon, Stephen G. Waxman, Sulayman D. Dib-Hajj

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Nav1.6 is the major sodium channel isoform at nodes of Ranvier in myelinated axons and, additionally, is distributed along unmyelinated C-fibers of sensory neurons. Thus, modulation of the sodium current produced by NavLe might significantly impact axonal conduction. Mitogen-activated protein kinases (MAPKs) are expressed in neurons and are activated after injury, for example, after sciatic nerve transection and hypoxia. Although the role of MAPK in signal transduction and in injury-induced regulation of gene expression is well established, the ability of these kinases to phosphorylate and modulate voltage-gated sodium channels has not been reported. Sequence analysis shows that Nav1.6 contains a putative MAP kinase-recognition module in the cytoplasmic loop (L1), which joins domains 1 and 2. We show in this study that sodium channels and p38 MAP kinase colocalize in rat brain tissue and that activated p38a phosphorylates L1 of Nav1.6, specifically at serine 553 (S553), in vitro. None of the other cytoplasmic loops and termini of the channel are phosphorylated by activated p38a in these assays. Activation of p38 in the neuronal ND7/23 cell line transfected with Nav1.6 leads to a significant reduction in the peak Nav1.6 current amplitude, without a detectable effect on gating properties. The substitution of S553 with alanine within L1 of the Nav1.6 channel prevents p38-mediated reduction of Nav1.6 current density. This is the first demonstration of MAPK phosphorylation and modulation of a voltage-gated sodium channel, and this modulation may represent an additional role for MAPK in regulating the neuronal response to injury.

Original languageEnglish (US)
Pages (from-to)6621-6630
Number of pages10
JournalJournal of Neuroscience
Volume25
Issue number28
DOIs
StatePublished - Jul 13 2005
Externally publishedYes

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NAV1.6 Voltage-Gated Sodium Channel
p38 Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinases
Voltage-Gated Sodium Channels
Sodium Channels
Serine
Wounds and Injuries
Ranvier's Nodes
Unmyelinated Nerve Fibers
MAP Kinase Signaling System
Gene Expression Regulation
Sensory Receptor Cells
Sciatic Nerve
Alanine
Sequence Analysis
Axons
Signal Transduction
Protein Isoforms
Phosphotransferases
Sodium

Keywords

  • Anisomycin
  • Ion channel
  • Kinase inhibitor
  • Patch clamp
  • Protein kinase
  • Stress

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase. / Wittmack, Ellen K.; Rush, Anthony M.; Hudmon, Andy; Waxman, Stephen G.; Dib-Hajj, Sulayman D.

In: Journal of Neuroscience, Vol. 25, No. 28, 13.07.2005, p. 6621-6630.

Research output: Contribution to journalArticle

Wittmack, Ellen K. ; Rush, Anthony M. ; Hudmon, Andy ; Waxman, Stephen G. ; Dib-Hajj, Sulayman D. / Voltage-gated sodium channel Nav1.6 is modulated by p38 mitogen-activated protein kinase. In: Journal of Neuroscience. 2005 ; Vol. 25, No. 28. pp. 6621-6630.
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