Role of Na V 1.9 in inflammatory mediator-induced activation of mouse airway vagal C-fibres.

The influence of NaV 1.9 on inflammatory mediator-induced activation of airway vagal nodose C-fibres was evaluated by comparing responses in wild-type vs. NaV 1.9-/- mice. A single cell rt-PCR analysis indicated that virtually all nodose C-fibre neurons expressed NaV 1.9 (SCN11A) mRNA. Using extracellular electrophysiological recordings in an isolated vagally-innervated mouse trachea-lung preparation, it was noted that mediators act via G-protein coupled receptors (PAR2), or ionotropic receptors (P2×3) were 70-85% less effective in evoking action potential discharge in the absence of NaV 1.9. However, there was no difference in action potential discharge between wild-type and NaV 1.9-/- when the stimulus was a rapid punctate mechanical stimulus. An analysis of the passive and active properties of isolated nodose neurons revealed no difference between neurons from wild-type and NaV 1.9 -/- mice, with the exception of a modest difference in the duration of the afterhyperpolarization (AHP). There was also no difference in the amount of current required to evoke action potentials (rheobase) or the action potential voltage threshold. The inward current evoked by the chemical mediator by a P2×3 agonist was the same in wild-type vs. NaV 1.9-/- neurons. However, the current was sufficient to evoke action potential only in the wild-type neurons. The data support the speculation that NaV 1.9 may be an attractive therapeutic target for inflammatory airway disease by selectively inhibiting inflammatory mediator-associated vagal C-fibre activation. KEY POINTS: Inflammatory mediators were much less effective in activating the terminals of vagal airway C-fibres in mice lacking NaV 1.9. The active and passive properties of nodose neurons were the same between wild-type neurons and NaV 1.9-/- neurons. Nerves lacking NaV 1.9 responded, normally, with action potential discharge to rapid punctate mechanical stimulation of the terminals or the rapid stimulation of the cell bodies with inward current injections. NaV 1.9 channels may be an attractive target to selectively inhibit vagal nociceptive C-fibre activation evoked by inflammatory mediators without blocking the nerves' responses to potentially hazardous stimuli associated with aspiration. Abstract Figure Legend: We tested the hypothesis that NaV 1.9 plays an important role in excitability of airway vagal nodose C-fibre. The data reveal that NaV 1.9 is important in the activation of nodose C-fibre terminals evoked by inflammatory mediators that act via GPCRs or ionotropic receptors but less critical in the activation by rapid punctate mechanical stimulation. The presence of NaV 1.9 does not influence the membrane properties of the neurons, nor their excitability as assessed by rapid injections of depolarizing current. NaV 1.9 provides an intriguing target for treating chronic coughing and excessive reflex bronchospasm and secretions associated with inflammatory airway disease. This article is protected by copyright. All rights reserved.