Channel synapse mediates neurotransmission of airway protective chemoreflexes

Area of Science:

• Neuroscience
• Cell Biology
• Physiology

Background:

• Neural reflexes in the throat are crucial for airway protection against aspiration and infection.
• The precise mechanisms underlying these reflexes, particularly in conditions like chronic cough, are not fully understood.
• Chronic cough represents a significant unmet clinical need due to its prevalence and the lack of effective treatments.

Purpose of the Study:

• To identify the cellular and molecular basis of chemosensory reflexes in the throat.
• To elucidate the role of specific cellular pathways in airway protective responses.
• To investigate the mechanisms contributing to hyperresponsiveness in airway reflexes.

Main Methods:

• Utilized a whole-body search for channel synapses and single-cell transcriptomics in mice.
• Investigated the function of Pou2f3+ cells and CALHM1/3 channels in throat chemosensation.
• Employed knockout models (Calhm3 and Pou2f3) and optogenetic stimulation to assess reflex activity.
• Examined the impact of aeroallergen exposure on reflex pathways.

Main Results:

• Discovered subclasses of Pou2f3+ chemosensory cells in the throat communicating with vagal neurons via CALHM1/3 channel synapses.
• These cells express T2Rs (taste receptors) that, upon stimulation by noxious chemicals, elicit swallow and cough-like expulsive reflexes.
• Reflexes were abolished in Calhm3 and Pou2f3 knockout mice and could be triggered by optogenetic stimulation.
• Aeroallergen exposure enhanced CALHM3-dependent expulsive reflexes, indicating a role in hyperresponsiveness.

Conclusions:

• Identified Pou2f3+ epithelial cells with CALHM channel synapses as key chemosensory end organs for airway protective reflexes.
• Established these cells as the sites of hyperresponsiveness in airway reflexes.
• Advanced mechanistic understanding of airway defense programs and highlighted potential therapeutic targets for conditions like chronic cough.