Functions of Slack potassium channels in neuropathic pain and itch
Final Report Abstract
Neuropathic pain and chronic itch affect millions of individuals worldwide, greatly impair their quality of life, and are inadequately treated with available drugs. Accumulating research has highlighted the prominent involvement of potassium (K+) channels in pain and itch processing, particularly in determining the excitability of sensory neurons. The K + channel Slack (also termed Kcnt1, KNa1.1 or Slo2.2) is highly expressed in non-peptidergic C fiber neurons, i.e. in a population of sensory neurons activated by painful and pruritic stimuli. Our preliminary work revealed that Slack selectively controls the sensory input in neuropathic pain states and during the processing of non-histaminergic itch. However, the detailed functional role of Slack and the mechanisms regulating its activity in remain poorly understood. The objective of the project was to evaluate the impact of Slack expressed in sensory neurons for the processing of neuropathic pain and itch, to assess specific mechanisms of Slack activation and modulation, and to characterize the effects of pharmacological Slack activation using mouse models. We found that the Slack-mediated K+ current (IK) is reduced in sensory neurons after peripheral nerve injury and that this contributes to neuropathic hypersensitivity. We also demonstrated that Slack is functionally coupled to P2X3 receptors and TRP-ankyrin type 1 (TRPA1) channels in sensory neurons. Moreover, we found that Slack in sensory neurons is important for itch processing, and that Slack activators relieve non-histaminergic itch. Therefore, targeting Slack could be a new approach for pharmacological treatment of pain and itch in future.
Publications
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Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing. International Journal of Molecular Sciences, 22(1), 405.
Lu, Ruirui; Metzner, Katharina; Zhou, Fangyuan; Flauaus, Cathrin; Balzulat, Annika; Engel, Patrick; Petersen, Jonas; Ehinger, Rebekka; Bausch, Anne; Ruth, Peter; Lukowski, Robert & Schmidtko, Achim
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Slack Potassium Channels Modulate TRPA1-Mediated Nociception in Sensory Neurons. Cells, 11(10), 1693.
Zhou, Fangyuan; Metzner, Katharina; Engel, Patrick; Balzulat, Annika; Sisignano, Marco; Ruth, Peter; Lukowski, Robert; Schmidtko, Achim & Lu, Ruirui
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Slick Potassium Channels Control Pain and Itch in Distinct Populations of Sensory and Spinal Neurons in Mice. Anesthesiology, 136(5), 802-822.
Flauaus, Cathrin; Engel, Patrick; Zhou, Fangyuan; Petersen, Jonas; Ruth, Peter; Lukowski, Robert; Schmidtko, Achim & Lu, Ruirui
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Slick potassium channels control pain and itch in distinct populations of sensory and spinal neurons in mice. IASP World Congress on Pain 2022 Toronto, Canada.
Engel P.; Flauaus C.; Zhou F.; Petersen J.; Ruth P.; Lukowski R.; Schmidtko A. & Lu R.
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Discovery of a new activator of Slack potassium channels with robust efficacy in models of histamine-independent and chronic itch. Cold Spring Harbor Laboratory.
Balzulat, Annika; Zhu, W. Felix; Flauaus, Cathrin; Hernandez-Olmos, Victor; Heering, Jan; Sethumadhavan, Sunesh; Dubiel, Mariam; Frank, Annika; Menge, Amelie; Hebchen, Maureen; Metzner, Katharina; Lu, Ruirui; Lukowski, Robert; Ruth, Peter; Knapp, Stefan; Müller, Susanne; Steinhilber, Dieter; Hänelt, Inga; Stark, Holger ... & Schmidtko, Achim
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Distinct functions of sodium-activated potassium channels in pain processing. International Congress on Neuropathic Pain 2023 Lisbon, Portugal.
Lu R.; Zhou F.; Engel P.; Flauaus C.; Metzner K. & Schmidtko A.
