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

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.

Authors

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

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Figure 3

Effects of retigabine on IM in mouse nodose neurons.

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Effects of retigabine on IM in mouse nodose neurons. (A) Representative ...
(A) Representative current recordings obtained from one of 7 mouse nodose neurons under the control condition (Ctrl), in the presence of 10 μM retigabine (RTG), and after subsequent addition of 10 μM XE991 in the presence of retigabine (RTG+XE). IM, as defined by XE991-sensitive currents, in the absence (Ctrl) and presence of retigabine, was derived from the original recordings shown in the upper panel by digital subtraction of the current recorded in the presence of XE991 from that obtained under the control condition, and by digital subtraction of the current recorded in the presence of both retigabine and XE991 from that recorded in the presence of retigabine alone. Dotted line represents the zero-current level. Where the instantaneous (Iin) and sustained (ISS) tail currents were measured is indicated. (B) Mean activation curves obtained from XE991-sensitive tail currents recorded in the absence and presence of 10 μM retigabine (n = 6). *P = 0.015 at –75 mV, 0.024 at –65 mV, 0.037 at –55 mV, 0.031 at –45 mV, and 0.031 at –35 mV by paired t test or Wilcoxon’s signed-rank test when normality test failed.