Role of NaV1.9 in inflammatory mediator-induced activation of mouse airway vagal C-fibres

The influence of Na(V)1.9 on inflammatory mediator-induced activation of airway vagal nodose C-fibres was evaluated by comparing responses in wild-type versus Na(V)1.9-/- mice. A single-cell RT-PCR analysis indicated that virtually all nodose C-fibre neurons expressed Na(V)1.9 (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 (P2x3) were 70-85% less effective in evoking action potential discharge in the absence of Na(V)1.9. However, there was no difference in action potential discharge between wild-type and Na(V)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 Na(V)1.9-/- 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 P2x3 agonist was the same in wild-type versus Na(V)1.9-/- neurons. However, the current was sufficient to evoke action potential only in the wild-type neurons. The data support the speculation that Na(V)1.9 could be an attractive therapeutic target for inflammatory airway disease by selectively inhibiting inflammatory mediator-associated vagal C-fibre activation.

Automated summary

The study evaluated the influence of Na(V)1.9 on the activation of airway vagal nodose C-fibres induced by inflammatory mediators. It was found that Na(V)1.9 played a crucial role in mediating the activation of C-fibres by G protein-coupled receptors and ionotropic receptors. However, Na(V)1.9 was not involved in the response to rapid punctate mechanical stimuli.