TRPV4-driven ATP release activates CFTR through ADORA2B and P2RY2 receptors in the airway epithelium

The CFTR chloride channel is essential for airway surface hydration and mucociliary clearance, and its activity is controlled by cAMP-dependent phosphorylation. We previously observed that pharmacological activation of the TRPV4 calcium channel stimulates CFTR, but the underlying mechanism remained unresolved. Here, we show that TRPV4 and CFTR are expressed in distinct epithelial cell types, indicating that TRPV4-induced CFTR activation occurs through a paracrine mechanism. Using a luciferase-based assay, we demonstrate that TRPV4 activation triggers ATP release at the apical surface. Pharmacological inhibition reveals that extracellular ATP activates CFTR through both P2Y2 purinergic and A2B adenosine receptors and that blocking these receptors nearly abolishes the response. These findings identify a TRPV4-ATP/adenosine-CFTR signaling axis that links mechanical and chemical stimuli to the control of airway surface hydration, with potential implications for mucociliary clearance and airway disease.