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

Authors

David Ritter, Department of Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Sidney Kimmel Medical College, Sidney Kimmel Medical College at Thomas Jefferson UniversityFollow
Benjamin M Zemel, Department of Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Sidney Kimmel Medical College, Sidney Kimmel Medical College at Thomas Jefferson UniversityFollow
Tamara J Hala, Department of Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson UniversityFollow
Michael E O'Leary, Cooper Medical School of Rowan University
Angelo C Lepore, Department of Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Sidney Kimmel Medical College, Sidney Kimmel Medical College at Thomas Jefferson UniversityFollow
Manuel Covarrubias, Department of Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University; Sidney Kimmel Medical College, Sidney Kimmel Medical College at Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

1-21-2015

Comments

This article has been peer reviewed. It was published in: Journal of Neuroscience.

Volume 35, Issue 3, 21 January 2015, Pages 1260-1273.

The published version is available at DOI: 10.1523/JNEUROSCI.1594-14.2015

Copyright © 2015 the authors.

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.

Recommended Citation

Ritter, David; Zemel, Benjamin M; Hala, Tamara J; O'Leary, Michael E; Lepore, Angelo C; and Covarrubias, Manuel, "Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury." (2015). Farber Institute for Neuroscience Faculty Papers. Paper 24.
https://jdc.jefferson.edu/farberneursofp/24

PubMed ID

25609640