Phosphorylation of sodium channel Nav1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons

Andy Hudmon, Jin Sung Choi, Lynda Tyrrell, Joel A. Black, Anthony M. Rush, Stephen G. Waxman, Sulayman D. Dib-Hajj

Research output: Contribution to journalArticle

112 Citations (Scopus)

Abstract

The sensory neuron-specific sodium channel Nav1.8 and p38 mitogen-activated protein kinase are potential therapeutic targets within nociceptive dorsal root ganglion (DRG) neurons in inflammatory, and possibly neuropathic, pain. Nav1.8 channels within nociceptive DRG neurons contribute most of the inward current underlying the depolarizing phase of action potentials. Nerve injury and inflammation of peripheral tissues cause p38 activation in DRG neurons, a process that may contribute to nociceptive neuron hyperexcitability, which is associated with pain. However, how substrates of activated p38 contribute to DRG neuron hyperexcitability is currently not well understood. We report here, for the first time, that Nav1.8 and p38 are colocalized in DRG neurons, that Nav1.8 within DRG neurons is a substrate for p38, and that direct phosphorylation of the Nav1.8 channel by p38 regulates its function in these neurons. We show that direct phosphorylation of Nav1.8 at two p38 phospho-acceptor serine residues on the L1 loop (S551 and S556) causes an increase in Nav1.8 current density that is not accompanied by changes in gating properties of the channel. Our study suggests a mechanism by which activated p38 contributes to inflammatory, and possibly neuropathic, pain through a p38-mediated increase of Nav1.8 current density.

Original languageEnglish
Pages (from-to)3190-3201
Number of pages12
JournalJournal of Neuroscience
Volume28
Issue number12
DOIs
StatePublished - Mar 19 2008

Fingerprint

Sodium Channels
Spinal Ganglia
p38 Mitogen-Activated Protein Kinases
Phosphorylation
Neurons
Neuralgia
Peripheral Nerve Injuries
Nociceptors
Sensory Receptor Cells
Serine
Action Potentials
Inflammation
Pain

Keywords

  • Anisomycin
  • Channel modulation
  • Inflammation
  • Kinase inhibitor
  • Nociception
  • SB203580
  • Stress

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Phosphorylation of sodium channel Nav1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. / Hudmon, Andy; Choi, Jin Sung; Tyrrell, Lynda; Black, Joel A.; Rush, Anthony M.; Waxman, Stephen G.; Dib-Hajj, Sulayman D.

In: Journal of Neuroscience, Vol. 28, No. 12, 19.03.2008, p. 3190-3201.

Research output: Contribution to journalArticle

Hudmon, Andy ; Choi, Jin Sung ; Tyrrell, Lynda ; Black, Joel A. ; Rush, Anthony M. ; Waxman, Stephen G. ; Dib-Hajj, Sulayman D. / Phosphorylation of sodium channel Nav1.8 by p38 mitogen-activated protein kinase increases current density in dorsal root ganglion neurons. In: Journal of Neuroscience. 2008 ; Vol. 28, No. 12. pp. 3190-3201.
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