Kv3.4 channel function and modulation in nociceptors: Novel insights into the pathophysiology of neuropathic pain

David M Ritter, Thomas Jefferson University


Chronic neuropathic pain affects millions of people worldwide; however, there remain few effective treatments for this condition. This is especially true in patients suffering spinal cord injury (SCI) where ~75% of them develop chronic pain. To treat chronic neuropathic pain, there needs to be an understanding of the molecular basis of nociception (basic pain sensation) and the maladaptive changes underlying the transition from acute to chronic pain. Dorsal root ganglia (DRG) neurons express Kv3.4 channels which are down-regulated in chronic pain. Additionally, Kv3.4 channels lose inactivation when phosphorylated by protein kinase C (PKC). In DRG neurons, the neurophysiological role and presence of PKC-dependent modulation of Kv3.4 channels was unknown. We hypothesized that phosphorylated Kv3.4 channels underlie a homeostatic antinociceptive mechanism that is lost during the transition to chronic pain. To test this, we used patch-clamp electrophysiology, molecular biology, immunohistochemistry and computational modeling. These results show that rat Kv3.4 channels are the dominant high voltage-activated K+ channels in nociceptors and activation of PKC induces loss of Kv3.4 channel inactivation that shortens the action potential (AP) duration. Transfection of Kv3.4 siRNA broadens the basal AP duration and inhibits PKC induced shortening of the AP duration. These results suggest that Kv3.4 channels control AP duration in an expression and phosphorylation dependent manner. In a rat SCI model of neuropathic pain, Kv3.4 channel inactivation is lost in both SCI and laminectomy control neurons one week post injury. Kv3.4 channel expression is then lost at two and six weeks post SCI and the neurons become hyperexcitable. However, laminectomy control neurons show restoration of Kv3.4 inactivation and expression at two and six weeks post surgery. Consistent with Kv3.4 siRNA knock-down experiments, APs from SCI neurons do not respond to PKC activation by shortening their duration, whereas laminectomy controls do. Finally, addition of Kv3.4 currents using the dynamic clamp method reverses the hyperexcitability in SCI neurons. Consistent with the hypothesis, these results suggest that nociceptors dynamically regulate Kv3.4 channel expression and phosphorylation after injury. We propose that Kv3.4 channels are strong therapeutic targets for novel analgesic strategies.

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Recommended Citation

Ritter, David M, "Kv3.4 channel function and modulation in nociceptors: Novel insights into the pathophysiology of neuropathic pain" (2013). ETD Collection for Thomas Jefferson University. AAI3588133.