Activation Mechanisms Of Airway Afferent Nerve

      Activation of primary afferent nerves is initiated by a stimulus-induced membrane depolarization referred to as a generator potential (GP). Bronchopulmonary C-fibers are “polymodal” meaning several disparate stimuli can evoke GPs in these nerves. The stimulus profile of the bronchopulmonary C-fibers is strictly dependent on whether the cell body is situated in the nodose or jugular ganglion. Among the ligand-gated ion channels involved in GPS, TRPA1 and TRPV1 serve to integrate many stimuli relevant to respiratory biology. TRPA1 can be gated by environmental irritants including ozone and TDI, and products of oxidative stress including oxidized prostanoids and hydroy- and oxy-nanenols. TRPV1 can be gated by inflammatory mediators that act via Gq GPCRs, certain eicosanoids, and decreases in pH. The GP leads to action potential (AP) discharge only if the depolarization reaches the voltage threshold for voltage gated sodium channels (NaVs). We have obtained both transcriptional evidence and electrophysiological evidence, that nociceptive C-fibers and non-nociceptive A-fibers innervating the airways express categorically and nearly exclusively NaV1.7, NaV 1.8 and NaV 1.9. NaV1.7 appears to be critically involved in setting voltage threshold, regulation of AP frequency, and AP conduction in these nerves. NaV 1.8 and 1.9 are suspected to play a key role in the increased excitability associated with airway inflammation.
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