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Research Articles, Cellular/Molecular

Regulation of Nociceptive Glutamatergic Signaling by Presynaptic Kv3.4 Channels in the Rat Spinal Dorsal Horn

Tanziyah Muqeem, Biswarup Ghosh, Vitor Pinto, Angelo C. Lepore and Manuel Covarrubias
Journal of Neuroscience 11 April 2018, 38 (15) 3729-3740; DOI: https://doi.org/10.1523/JNEUROSCI.3212-17.2018
Tanziyah Muqeem
1Department of Neuroscience and Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, 2Jefferson College of Biomedical Sciences at Thomas Jefferson University, Philadelphia, Pennsylvania 19107,
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Biswarup Ghosh
1Department of Neuroscience and Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, 2Jefferson College of Biomedical Sciences at Thomas Jefferson University, Philadelphia, Pennsylvania 19107,
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Vitor Pinto
3Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, 4710-057, Braga, Portugal, and 4ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
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Angelo C. Lepore
1Department of Neuroscience and Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, 2Jefferson College of Biomedical Sciences at Thomas Jefferson University, Philadelphia, Pennsylvania 19107,
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Manuel Covarrubias
1Department of Neuroscience and Vickie and Jack Farber Institute for Neuroscience, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania 19107, 2Jefferson College of Biomedical Sciences at Thomas Jefferson University, Philadelphia, Pennsylvania 19107,
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Abstract

Presynaptic voltage-gated K+ (Kv) channels in dorsal root ganglion (DRG) neurons are thought to regulate nociceptive synaptic transmission in the spinal dorsal horn. However, the Kv channel subtypes responsible for this critical role have not been identified. The Kv3.4 channel is particularly important because it is robustly expressed in DRG nociceptors, where it regulates action potential (AP) duration. Furthermore, Kv3.4 dysfunction is implicated in the pathophysiology of neuropathic pain in multiple pain models. We hypothesized that, through their ability to modulate AP repolarization, Kv3.4 channels in DRG nociceptors help to regulate nociceptive synaptic transmission. To test this hypothesis, we investigated Kv3.4 immunoreactivity (IR) in the rat cervical superficial dorsal horn (sDH) in both sexes and implemented an intact spinal cord preparation to investigate glutamatergic synaptic currents from second order neurons in the sDH under conditions that selectively inhibit the Kv3.4 current. We found presynaptic Kv3.4 IR in peptidergic and nonpeptidergic nociceptive fibers of the sDH. The Kv3.4 channel is hypersensitive to 4-aminopyridine and tetraethylammonium (TEA). Accordingly, 50 μm 4-aminopyridine and 500 μm TEA significantly prolong the AP, slow the maximum rate of repolarization in small-diameter DRG neurons, and potentiate monosynaptic excitatory postsynaptic currents (EPSCs) in dorsal horn laminae I and II through a presynaptic mechanism. In contrast, highly specific inhibitors of BK, Kv7, and Kv1 channels are less effective modulators of the AP and have little to no effect on EPSCs. The results strongly suggest that presynaptic Kv3.4 channels are major regulators of nociceptive synaptic transmission in the spinal cord.

SIGNIFICANCE STATEMENT Intractable neuropathic pain can result from disease or traumatic injury and many studies have been conducted to determine the underlying pathophysiological changes. Voltage-gated ion channels, including the K+ channel Kv3.4, are dysregulated in multiple pain models. Kv3.4 channels are ubiquitously expressed in the dorsal root ganglion (DRG), where they are major regulators of DRG excitability. However, little is known about the ionic mechanisms that regulate nociceptive synaptic transmission at the level of the first synapse in the spinal cord, which is critical to pain transmission in both intact and pathological states. Here, we show that Kv3.4 channels have a significant impact on glutamatergic synaptic transmission in the dorsal horn, further illuminating its potential as a molecular pain therapeutic target.

  • Kv channel
  • pain transduction
  • spinal cord
  • synaptic transmission
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The Journal of Neuroscience: 38 (15)
Journal of Neuroscience
Vol. 38, Issue 15
11 Apr 2018
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Regulation of Nociceptive Glutamatergic Signaling by Presynaptic Kv3.4 Channels in the Rat Spinal Dorsal Horn
Tanziyah Muqeem, Biswarup Ghosh, Vitor Pinto, Angelo C. Lepore, Manuel Covarrubias
Journal of Neuroscience 11 April 2018, 38 (15) 3729-3740; DOI: 10.1523/JNEUROSCI.3212-17.2018

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Regulation of Nociceptive Glutamatergic Signaling by Presynaptic Kv3.4 Channels in the Rat Spinal Dorsal Horn
Tanziyah Muqeem, Biswarup Ghosh, Vitor Pinto, Angelo C. Lepore, Manuel Covarrubias
Journal of Neuroscience 11 April 2018, 38 (15) 3729-3740; DOI: 10.1523/JNEUROSCI.3212-17.2018
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Keywords

  • Kv channel
  • pain transduction
  • spinal cord
  • synaptic transmission

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JNeurosci   Print ISSN: 0270-6474   Online ISSN: 1529-2401