Channel synapse mediates neurotransmission of airway protective chemoreflexes

Abstract

Neural reflexes to chemicals in the throat protect the airway from aspiration and infection. Mechanistic understanding of these reflexes remains premature, exemplified by chronic cough—a sensitized cough reflex—being a prevalent unmet clinical need. Here, in mice, a whole-body search for channel synapses—featuring CALHM1/3 channel-mediated neurotransmitter release—and single-cell transcriptomics uncovered subclasses of the Pou2f3+ chemosensory cell family in the throat communicating with vagal neurons via this synapse. They express G protein-coupled receptors (GPCRs) for noxious chemicals, T2Rs, which upon stimulation trigger swallow and cough-like expulsive reflexes in the hypopharynx and larynx, respectively. These reflexes were abolished by Calhm3 and Pou2f3 knockout and could be triggered by targeted optogenetic stimulation. Furthermore, aeroallergen exposure augmented CALHM3-dependent expulsive reflex. This study identifies Pou2f3+ epithelial cells with channel synapses as chemosensory end organs of airway protective reflexes and sites of their hyperresponsiveness, advancing mechanistic understanding of airway defense programs with distinct therapeutic potential.