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Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability

Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family members that share the same pathogenic gain-of...

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Autores principales: Estacion, Mark, Liu, Shujun, Cheng, Xiaoyang, Dib-Hajj, Sulayman, Waxman, Stephen G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10008904/
https://www.ncbi.nlm.nih.gov/pubmed/36923357
http://dx.doi.org/10.3389/fphar.2023.1138556
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author Estacion, Mark
Liu, Shujun
Cheng, Xiaoyang
Dib-Hajj, Sulayman
Waxman, Stephen G.
author_facet Estacion, Mark
Liu, Shujun
Cheng, Xiaoyang
Dib-Hajj, Sulayman
Waxman, Stephen G.
author_sort Estacion, Mark
collection PubMed
description Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family members that share the same pathogenic gain-of-function Nav1.7 mutation that confers hyperexcitability on pain-signaling dorsal root ganglion (DRG) neurons. In each of these kindreds, the pain-resilient individual carried a gain-of-function variant in Kv7.2 or Kv7.3, two potassium channels that stabilize membrane potential and reduce excitability. Our observation in this molecular genetic study that these gain-of-function Kv7.2 and 7.3 variants reduce DRG neuron excitability suggests that agents that activate or open Kv7 channels should attenuate sensory neuron firing. In the present study, we assess the effects on sensory neuron excitability of three Kv7 modulators—retigabine (Kv7.2 thru Kv7.5 activator), ICA-110381 (Kv7.2/Kv7.3 specific activator), and as a comparator ML277 (Kv7.1 specific activator)—in a “human-pain-in-a-dish” model (human iPSC-derived sensory neurons, iPSC-SN). Multi-electrode-array (MEA) recordings demonstrated inhibition of firing with retigabine and ICA-110381 (but not with ML277), with the concentration-response curve indicating that retigabine can achieve a 50% reduction of firing with sub-micromolar concentrations. Current-clamp recording demonstrated that retigabine hyperpolarized iPSC-SN resting potential and increased threshold. This study implicates Kv7.2/Kv7.3 channels as effective modulators of sensory neuron excitability, and suggest that compounds that specifically target Kv7.2/Kv7.3 currents in sensory neurons, including human sensory neurons, might provide an effective approach toward pain relief.
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spelling pubmed-100089042023-03-14 Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability Estacion, Mark Liu, Shujun Cheng, Xiaoyang Dib-Hajj, Sulayman Waxman, Stephen G. Front Pharmacol Pharmacology Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain than other family members that share the same pathogenic gain-of-function Nav1.7 mutation that confers hyperexcitability on pain-signaling dorsal root ganglion (DRG) neurons. In each of these kindreds, the pain-resilient individual carried a gain-of-function variant in Kv7.2 or Kv7.3, two potassium channels that stabilize membrane potential and reduce excitability. Our observation in this molecular genetic study that these gain-of-function Kv7.2 and 7.3 variants reduce DRG neuron excitability suggests that agents that activate or open Kv7 channels should attenuate sensory neuron firing. In the present study, we assess the effects on sensory neuron excitability of three Kv7 modulators—retigabine (Kv7.2 thru Kv7.5 activator), ICA-110381 (Kv7.2/Kv7.3 specific activator), and as a comparator ML277 (Kv7.1 specific activator)—in a “human-pain-in-a-dish” model (human iPSC-derived sensory neurons, iPSC-SN). Multi-electrode-array (MEA) recordings demonstrated inhibition of firing with retigabine and ICA-110381 (but not with ML277), with the concentration-response curve indicating that retigabine can achieve a 50% reduction of firing with sub-micromolar concentrations. Current-clamp recording demonstrated that retigabine hyperpolarized iPSC-SN resting potential and increased threshold. This study implicates Kv7.2/Kv7.3 channels as effective modulators of sensory neuron excitability, and suggest that compounds that specifically target Kv7.2/Kv7.3 currents in sensory neurons, including human sensory neurons, might provide an effective approach toward pain relief. Frontiers Media S.A. 2023-02-27 /pmc/articles/PMC10008904/ /pubmed/36923357 http://dx.doi.org/10.3389/fphar.2023.1138556 Text en Copyright © 2023 Estacion, Liu, Cheng, Dib-Hajj and Waxman. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Estacion, Mark
Liu, Shujun
Cheng, Xiaoyang
Dib-Hajj, Sulayman
Waxman, Stephen G.
Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
title Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
title_full Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
title_fullStr Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
title_full_unstemmed Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
title_short Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
title_sort kv7-specific activators hyperpolarize resting membrane potential and modulate human ipsc-derived sensory neuron excitability
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10008904/
https://www.ncbi.nlm.nih.gov/pubmed/36923357
http://dx.doi.org/10.3389/fphar.2023.1138556
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