Role of Na_V1.9 in inflammatory mediator-induced activation of mouse airway vagal C-fibres

Abstract: The influence of Na_V1.9 on inflammatory mediator-induced activation of airway vagal nodose C-fibres was evaluated by comparing responses in wild-type versus Na_V1.9-/- mice. A single-cell RT-PCR analysis indicated that virtually all nodose C-fibre neurons expressed Na_V1.9 (SCN11A) mRNA. Using extracellular electrophysiological recordings in an isolated vagally innervated mouse trachea–lung preparation, it was noted that mediators acting 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 Na_V1.9. However, there was no difference in action potential discharge between wild-type and Na_V1.9-/- 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 Na_V1.9-/- mice, with the exception of a modest difference in the duration of the afterhyperpolarization. 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 versus Na_V1.9-/- neurons. However, the current was sufficient to evoke action potential only in the wild-type neurons. The data support the speculation that Na_V1.9 could be an attractive therapeutic target for inflammatory airway disease by selectively inhibiting inflammatory mediator-associated vagal C-fibre activation. (Figure presented.). Key points: Inflammatory mediators were much less effective in activating the terminals of vagal airway C-fibres in mice lacking Na_V1.9. The active and passive properties of nodose neurons were the same between wild-type neurons and Na_V1.9-/- neurons. Nerves lacking Na_V1.9 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. Na_V1.9 channels could be an attractive target to selectively inhibit vagal nociceptive C-fibre activation evoked by inflammatory mediators without blocking the nerves’ responses to the potentially hazardous stimuli associated with aspiration.