Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury

David M. Ritter, Benjamin M. Zemel, Tamara J. Hala, Michael E. O'Leary, Angelo C. Lepore, Manuel Covarrubias

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Abstract

Spinal cord injury (SCI) patients develop chronic pain involving poorly understood central and peripheral mechanisms. Because dysregulation of the voltage-gated Kv3.4 channel has been implicated in the hyperexcitable state of dorsal root ganglion (DRG) neurons following direct injury of sensory nerves, we asked whether such a dysregulation also plays a role in SCI. Kv3.4 channels are expressed in DRG neurons, where they help regulate action potential (AP) repolarization in a manner that depends on the modulation of inactivation by protein kinase C (PKC)-dependent phosphorylation of the channel’s inactivation domain. Here, we report that, 2 weeks after cervical hemicontusion SCI, injured rats exhibit contralateral hypersensitivity to stimuli accompanied by accentuated repetitive spiking in putative DRG nociceptors. Also in these neurons at 1 week after laminectomy and SCI, Kv3.4 channel inactivation is impaired compared with naive nonsurgical controls. At 2– 6 weeks after laminectomy, however, Kv3.4 channel inactivation returns to naive levels. Conversely, Kv3.4 currents at 2– 6 weeks post-SCI are downregulated and remain slow-inactivating. Immunohistochemistry indicated that downregulation mainly resulted from decreased surface expression of the Kv3.4 channel, as whole-DRG-protein and single-cell mRNA transcript levels did not change. Furthermore, consistent with Kv3.4 channel dysregulation, PKC activation failed to shorten the AP duration of small-diameter DRG neurons. Finally, re-expressing synthetic Kv3.4 currents under dynamic clamp conditions dampened repetitive spiking in the neurons from SCI rats. These results suggest a novel peripheral mechanism of post-SCI pain sensitization implicating Kv3.4 channel dysregulation and potential Kv3.4-based therapeutic interventions.

Original languageEnglish (US)
Pages (from-to)1260-1273
Number of pages14
JournalJournal of Neuroscience
Volume35
Issue number3
DOIs
StatePublished - Jan 21 2015

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Spinal Ganglia
Spinal Cord Injuries
Neurons
Laminectomy
Protein Kinase C
Action Potentials
Down-Regulation
Nociceptors
Chronic Pain
Hypersensitivity
Immunohistochemistry
Phosphorylation
Pain
Messenger RNA
Wounds and Injuries

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Medicine(all)

Cite this

Ritter, David M. ; Zemel, Benjamin M. ; Hala, Tamara J. ; O'Leary, Michael E. ; Lepore, Angelo C. ; Covarrubias, Manuel. / Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 3. pp. 1260-1273.
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Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury. / Ritter, David M.; Zemel, Benjamin M.; Hala, Tamara J.; O'Leary, Michael E.; Lepore, Angelo C.; Covarrubias, Manuel.

In: Journal of Neuroscience, Vol. 35, No. 3, 21.01.2015, p. 1260-1273.

Research output: Contribution to journalArticle

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AU - Ritter, David M.

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