The Role of Kv3.4 Channels in the Neurotransmission of Pain
Pain signaling is an important biological process that is poorly understood. The mechanisms of physiological and pathophysiological processes that contribute to pain are under active investigation. Amongst those mechanisms, ion channels, and, in particular, voltage-gated ion channels are known as critical players in the propagation and regulation of signaling in the pain pathway. Kv3.4 channels are major regulators of excitability in the dorsal root ganglion (DRG) neuron, the first neuron in the pain pathway. Previous studies have indicated the importance of Kv3.4 channels in homeostatic pain regulation as well as in chronic pain in a spinal cord injury (SCI) model. Kv3.4 currents are thought to undergo maladaptive phosphorylation that causes current attenuation, which can contribute to the development of chronic pain. However, it was not known whether Kv3.4 currents might contribute to the propagation of nociceptive signaling further up in the pain pathway, namely between the DRG neuron and its targets in the spinal cord dorsal horn, the second neuron in the pathway. Studies in other regions of the nervous system have suggested a key role of Kv3 channels in this process despite the existence of other K+ channels in presynaptic nerve terminals. We set out to investigate whether Kv3.4 channels might regulate synaptic transmission at the level of the first synapse in the pain pathway, and whether Kv3.4 channel recombinant mutants can affect the action potential (AP) of DRG neurons. We studied this using electrophysiology, optogenetics, and immunohistochemistry. Our results suggest that Kv3.4 channels are expressed in both rat and mouse spinal cord dorsal horn, and that they co-localize with known markers of nociceptors where they may be positioned to regulate synaptic transmission between DRG and dorsal horn neurons. Using an intact spinal cord preparation as well as spinal cord slices, we then probed how pharmacological inhibition of Kv3.4 channels might impact nociceptive synaptic signaling. We found that Kv3.4 channel inhibition resulted in consistent potentiation of excitatory postsynaptic currents (EPSCs) measured in dorsal horn neurons, whereas specific blockers of other K+ channels had little to no effect. In exploratory experiments, we also found that the DRG AP can be modulated by expressing Kv3.4 channels, which opens opportunities for translational applications that might help treat pain disorders. Together, these results indicate that the Kv3.4 channel has a major role in nociceptive synaptic signaling at the level of the first synapse in the pain pathway through its ability to modulate the presynaptic DRG AP, thereby regulating neurotransmitter release and transmission of painful stimuli to higher order regions of the pain pathway.
Muqeem, Tanziyah, "The Role of Kv3.4 Channels in the Neurotransmission of Pain" (2020). ETD Collection for Thomas Jefferson University. AAI13904511.