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KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity
Hui Sun, … , Lu-Yuan Lee, Bradley J. Undem
Hui Sun, … , Lu-Yuan Lee, Bradley J. Undem
Published February 5, 2019
Citation Information: JCI Insight. 2019;4(5):e124467. https://doi.org/10.1172/jci.insight.124467.
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Research Article Pulmonology

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

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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.

Authors

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

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Figure 4

Effects of retigabine and/or XE991 on resting potentials and spontaneous AP firing in mouse nodose neurons.

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Effects of retigabine and/or XE991 on resting potentials and spontaneous...
(A) Representative recordings of membrane potential obtained from 2 different neurons. Bath application of retigabine and XE991 is indicated by the horizontal bars at the top of the recordings. Dotted lines indicate control resting potential (RP) levels. (B) Quantification of RP values measured from 2 groups of neurons (n = 6 and 12, respectively) under the control condition (Ctrl), in the presence of retigabine (RTG), and after washout of retigabine (WO), or after subsequent addition of XE991 to retigabine-containing bath solution (RTG+XE) as in the examples shown in A. *P = 0.006, **P < 0.001. (C) Representative recordings of membrane potential obtained from 2 different neurons. Dotted lines indicate control RP levels. The break symbol in the lower trace represents a 5-minute interval during which the cell was repetitively stimulated to fire the APs with suprathreshold current injections in the constant presence of XE991. (D) Quantification of RP values measured from 2 groups of neurons (n = 8 and 10, respectively) at baseline (Ctrl), in the presence of XE991 (XE), and after addition of retigabine in the presence of XE991 (XE+RTG), or after washout of XE991 (WO). *P = 0.004, **P < 0.001. (E) Representative recordings of membrane potential showing the effects of retigabine and XE991 on spontaneous AP firing. Box-and-whisker plots in B and D: Horizontal lines of boxes represent 25th percentile, median, and 75th percentile. Whiskers represent 5th/95th percentile. Filled circles represent mean values. Statistical significance was determined by 1-way repeated-measures ANOVA with Holm-Šídák test as a post hoc analysis.

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