title: Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury.
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.
authors.affiliation: Department of Neuroscience, Farber Institute for Neuroscience, and Neuroscience Graduate Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and.
authors.forename: David M
authors.initials: DM
authors.lastname: Ritter
authors.affiliation: Department of Neuroscience, Farber Institute for Neuroscience, and Neuroscience Graduate Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Zemel
authors.affiliation: Department of Neuroscience, Farber Institute for Neuroscience, and.
authors.forename: Tamara J
authors.identifier: http://orcid.org/0000-0001-5851-271X
authors.initials: TJ
authors.lastname: Hala
authors.affiliation: Cooper Medical School of Rowan University, Camden, New Jersey 08103.
authors.forename: Michael E
authors.initials: ME
authors.lastname: O'Leary
authors.affiliation: Department of Neuroscience, Farber Institute for Neuroscience, and Neuroscience Graduate Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and.
authors.forename: Angelo C
authors.initials: AC
authors.lastname: Lepore
authors.affiliation: Department of Neuroscience, Farber Institute for Neuroscience, and Neuroscience Graduate Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and manuel.covarrubias@jefferson.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Covarrubias
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000502:physiology*; D010146:Pain / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D051670:Shaw Potassium Channels / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology
chemical_list: C492014:Kcnc4 protein, rat; D051670:Shaw Potassium Channels
keywords: Kv3.4; pain; potassium channels; protein kinase C; spinal cord injury