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Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron
Mark Estacion1,2, Shujun Liu1,2, Xiaoyang Cheng1,2
1Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, United States.
Frontiers in Pharmacology
|March 16, 2023
Summary
Individuals with high pain tolerance possess specific genetic variants in Kv7.2/Kv7.3 potassium channels. Activating these channels may offer new pain relief strategies by reducing sensory neuron excitability.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Chronic pain is a widespread condition with limited treatment options.
- Genetic variations can influence pain perception and resilience.
- Gain-of-function mutations in Nav1.7 channels increase sensory neuron excitability, contributing to pain.
Purpose of the Study:
- To investigate the role of Kv7.2 and Kv7.3 potassium channels in pain resilience.
- To evaluate the efficacy of Kv7 channel modulators in reducing sensory neuron excitability.
Main Methods:
- Studied two family cohorts with individuals exhibiting pain resilience despite a Nav1.7 mutation.
- Utilized a human induced pluripotent stem cell-derived sensory neuron (iPSC-SN) model.
- Assessed Kv7 modulators (retigabine, ICA-110381, ML277) using multi-electrode array (MEA) and current-clamp recordings.
Main Results:
- Pain-resilient individuals carried gain-of-function variants in Kv7.2 or Kv7.3 channels.
- Retigabine and ICA-110381 inhibited iPSC-SN firing, while ML277 did not.
- Retigabine demonstrated potent inhibition at sub-micromolar concentrations, hyperpolarizing neurons and increasing firing threshold.
Conclusions:
- Gain-of-function Kv7.2/Kv7.3 variants reduce sensory neuron excitability, conferring pain resilience.
- Kv7.2/Kv7.3 channels are viable targets for pain management.
- Compounds specifically targeting Kv7.2/Kv7.3 in sensory neurons may offer novel pain relief therapies.
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