KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity

Hui Sun, An Hsuan Lin, Fei Ru, Mayur J. Patil, Sonya Meeker, Lu Yuan Lee, Bradley J Undem

Research output: Contribution to journalArticle

Abstract

Increased airway vagal sensory C-fiber activity contributes to the symptoms of inflammatory airway diseases. The KCNQ/Kv7/M-channel is a well-known determinant of neuronal excitability, yet whether it regulates the activity of vagal bronchopulmonary C-fibers and airway reflex sensitivity remains unknown. Here we addressed this issue using single-cell RT-PCR, patch clamp technique, extracellular recording of single vagal nerve fibers innervating the mouse lungs, and telemetric recording of cough in free-moving mice. Single-cell mRNA analysis and biophysical properties of M-current (IM) suggest that KCNQ3/Kv7.3 is the major M-channel subunit in mouse nodose neurons. The M-channel opener retigabine negatively shifted the voltage-dependent activation of IM, leading to membrane hyperpolarization, increased rheobase, and suppression of both evoked and spontaneous action potential (AP) firing in nodose neurons in an M-channel inhibitor XE991-sensitive manner. Retigabine also markedly suppressed the α,β-methylene ATP-induced AP firing in nodose C-fiber terminals innervating the mouse lungs, and coughing evoked by irritant gases in awake mice. In conclusion, KCNQ/M-channels play a role in regulating the excitability of vagal airway C-fibers at both the cell soma and nerve terminals. Drugs that open M-channels in airway sensory afferents may relieve the sufferings associated with pulmonary inflammatory diseases such as chronic coughing.

Original languageEnglish (US)
JournalJCI insight
Volume4
Issue number5
DOIs
StatePublished - Mar 7 2019

Fingerprint

Unmyelinated Nerve Fibers
Cough
Neurons
Action Potentials
Single-Cell Analysis
Lung
Irritants
Carisoprodol
Patch-Clamp Techniques
Nerve Fibers
Lung Diseases
Reflex
Adenosine Triphosphate
Gases
Polymerase Chain Reaction
Messenger RNA
Membranes
Pharmaceutical Preparations

Keywords

  • Potassium channels
  • Pulmonology

Cite this

KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity. / Sun, Hui; Lin, An Hsuan; Ru, Fei; Patil, Mayur J.; Meeker, Sonya; Lee, Lu Yuan; Undem, Bradley J.

In: JCI insight, Vol. 4, No. 5, 07.03.2019.

Research output: Contribution to journalArticle

@article{9f389b39f08d48af81c87a4ab6af4dfb,
title = "KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity",
abstract = "Increased airway vagal sensory C-fiber activity contributes to the symptoms of inflammatory airway diseases. The KCNQ/Kv7/M-channel is a well-known determinant of neuronal excitability, yet whether it regulates the activity of vagal bronchopulmonary C-fibers and airway reflex sensitivity remains unknown. Here we addressed this issue using single-cell RT-PCR, patch clamp technique, extracellular recording of single vagal nerve fibers innervating the mouse lungs, and telemetric recording of cough in free-moving mice. Single-cell mRNA analysis and biophysical properties of M-current (IM) suggest that KCNQ3/Kv7.3 is the major M-channel subunit in mouse nodose neurons. The M-channel opener retigabine negatively shifted the voltage-dependent activation of IM, leading to membrane hyperpolarization, increased rheobase, and suppression of both evoked and spontaneous action potential (AP) firing in nodose neurons in an M-channel inhibitor XE991-sensitive manner. Retigabine also markedly suppressed the α,β-methylene ATP-induced AP firing in nodose C-fiber terminals innervating the mouse lungs, and coughing evoked by irritant gases in awake mice. In conclusion, KCNQ/M-channels play a role in regulating the excitability of vagal airway C-fibers at both the cell soma and nerve terminals. Drugs that open M-channels in airway sensory afferents may relieve the sufferings associated with pulmonary inflammatory diseases such as chronic coughing.",
keywords = "Potassium channels, Pulmonology",
author = "Hui Sun and Lin, {An Hsuan} and Fei Ru and Patil, {Mayur J.} and Sonya Meeker and Lee, {Lu Yuan} and Undem, {Bradley J}",
year = "2019",
month = "3",
day = "7",
doi = "10.1172/jci.insight.124467",
language = "English (US)",
volume = "4",
journal = "JCI insight",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity

AU - Sun, Hui

AU - Lin, An Hsuan

AU - Ru, Fei

AU - Patil, Mayur J.

AU - Meeker, Sonya

AU - Lee, Lu Yuan

AU - Undem, Bradley J

PY - 2019/3/7

Y1 - 2019/3/7

N2 - Increased airway vagal sensory C-fiber activity contributes to the symptoms of inflammatory airway diseases. The KCNQ/Kv7/M-channel is a well-known determinant of neuronal excitability, yet whether it regulates the activity of vagal bronchopulmonary C-fibers and airway reflex sensitivity remains unknown. Here we addressed this issue using single-cell RT-PCR, patch clamp technique, extracellular recording of single vagal nerve fibers innervating the mouse lungs, and telemetric recording of cough in free-moving mice. Single-cell mRNA analysis and biophysical properties of M-current (IM) suggest that KCNQ3/Kv7.3 is the major M-channel subunit in mouse nodose neurons. The M-channel opener retigabine negatively shifted the voltage-dependent activation of IM, leading to membrane hyperpolarization, increased rheobase, and suppression of both evoked and spontaneous action potential (AP) firing in nodose neurons in an M-channel inhibitor XE991-sensitive manner. Retigabine also markedly suppressed the α,β-methylene ATP-induced AP firing in nodose C-fiber terminals innervating the mouse lungs, and coughing evoked by irritant gases in awake mice. In conclusion, KCNQ/M-channels play a role in regulating the excitability of vagal airway C-fibers at both the cell soma and nerve terminals. Drugs that open M-channels in airway sensory afferents may relieve the sufferings associated with pulmonary inflammatory diseases such as chronic coughing.

AB - Increased airway vagal sensory C-fiber activity contributes to the symptoms of inflammatory airway diseases. The KCNQ/Kv7/M-channel is a well-known determinant of neuronal excitability, yet whether it regulates the activity of vagal bronchopulmonary C-fibers and airway reflex sensitivity remains unknown. Here we addressed this issue using single-cell RT-PCR, patch clamp technique, extracellular recording of single vagal nerve fibers innervating the mouse lungs, and telemetric recording of cough in free-moving mice. Single-cell mRNA analysis and biophysical properties of M-current (IM) suggest that KCNQ3/Kv7.3 is the major M-channel subunit in mouse nodose neurons. The M-channel opener retigabine negatively shifted the voltage-dependent activation of IM, leading to membrane hyperpolarization, increased rheobase, and suppression of both evoked and spontaneous action potential (AP) firing in nodose neurons in an M-channel inhibitor XE991-sensitive manner. Retigabine also markedly suppressed the α,β-methylene ATP-induced AP firing in nodose C-fiber terminals innervating the mouse lungs, and coughing evoked by irritant gases in awake mice. In conclusion, KCNQ/M-channels play a role in regulating the excitability of vagal airway C-fibers at both the cell soma and nerve terminals. Drugs that open M-channels in airway sensory afferents may relieve the sufferings associated with pulmonary inflammatory diseases such as chronic coughing.

KW - Potassium channels

KW - Pulmonology

UR - http://www.scopus.com/inward/record.url?scp=85062591295&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062591295&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.124467

DO - 10.1172/jci.insight.124467

M3 - Article

C2 - 30721152

AN - SCOPUS:85062591295

VL - 4

JO - JCI insight

JF - JCI insight

SN - 2379-3708

IS - 5

ER -