Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing

Ruirui Lu, Katharina Metzner, Fangyuan Zhou, Cathrin Flauaus, Annika Balzulat, Patrick Engel, Jonas Petersen, Rebekka Ehinger, Anne Bausch, Peter Ruth, Robert Lukowski, Achim Schmidtko
2021 International Journal of Molecular Sciences  
The sodium-activated potassium channel Slack (KNa1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (IKNa) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated IKNa in sensory
more » ... ed IKNa in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated IKNa may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.
doi:10.3390/ijms22010405 pmid:33401689 fatcat:okqgp7ifs5czlk7b6f3fqewqv4