Work

Targeting cyclic-AMP/phosphodiesterase signaling to quiet nasal tuft cell calcium responses

Year: 2026

Type: preprint

Abstract: Background Airway tuft cells, also called solitary chemosensory cells, are enriched in nasal polyps and are likely the main epithelial source of interleukin-25 (IL-25) in chronic rhinosinusitis with nasal polyps (CRSwNP). Tuft cells are activated through G protein-coupled receptors (GPCRs) that signal through Ca 2+ . These receptors may also lower cyclic AMP (cAMP), but whether the cAMP pathway can be used to suppress tuft cell responses is unknown. Methods Ca 2+ and cAMP were measured by live cell imaging in isolated Trpm5-GFP mouse nasal tuft cells, and Ca 2+ responses were measured in primary human nasal epithelial air-liquid interface (ALI) cultures from patients with CRSwNP. Defensin and IL-25 release were measured by ELISA and ciliary beat frequency (CBF) by high-speed imaging. Phosphodiesterase (PDE) expression was assessed using publicly available single cell RNA sequencing datasets. Results Agonists of bitter taste receptors (T2Rs), the succinate receptor SUCNR1, and the A1 adenosine receptor increased Ca 2+ in GFP-positive mouse nasal tuft cells. T2R and A1 receptor stimulation also lowered cAMP, and these decreases were blocked by pertussis toxin. Glucose, which activates taste family 1 receptors, increased cAMP. Tuft cells were enriched for Pde2a . PDE2A-selective inhibitors (PF-05180999 and BAY 60-7550) increased cAMP and reduced agonist-evoked Ca 2+ responses in mouse tuft cells. In human nasal ALIs, both compounds reduced denatonium-evoked Ca 2+ responses, defensin release, and IL-25 release without increasing CBF. Conclusions GPCRs that activate nasal tuft cells also lower cAMP, and by raising cAMP through PDE2A inhibition, tuft cell Ca 2+ signaling and IL-25 release were reduced in vitro.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.10.21.760783