Fig. 2. Proposed mechanisms of luminal ATP-P2Y signaling during acid exposure.

Acid exposure increases luminal ATP concentration. ATP stimulates P2Y receptors on the apical membrane of epithelial cells, and then increases intracellular Ca²⁺ concentration. Ca²⁺ activates dual oxidase 2 (Duox2), which generates H₂O₂ in the lumen. H₂O₂ activates cytosolic phospholipase A2 (cPLA₂), followed by cyclooxygenase (COX)-mediated prostaglandin E2 (PGE₂) synthesis. PGE₂ stimulates EP4 receptor, followed by cystic fibrosis transmembrane conductance regulator (CFTR) stimulation, increasing protective HCO₃⁻ secretion. On the other hand, toll-like receptor (TLR) ligand, Pam3 or lipopolysaccharide (LPS), and nucleotide-binding oligomerization domain 2 (NOD2) ligand muramyl dipeptide (MDP) coordinately increases H₂O₂ production with enhanced ATP release and IkB kinase (IKK) activation. This bacterial sensing pathway also increases PGE₂ production and stimulates HCO₃⁻ secretion.