FIGURE 1.

Model of acid/CO₂-sensing mechanisms in the duodenum. The scheme summarizes how H⁺/CO₂ traverses the mucosa and is sensed by the duodenum. (1) Luminal H⁺ from the stomach is neutralized with the secreted HCO₃⁻ in the duodenum, generating CO₂, which is facilitated by extracellular carbonic anhydrase (CA). (2) CO₂ diffuses into the cytoplasm through the apical membrane of the epithelial cells. (3) CO₂ is converted into H⁺ and HCO₃⁻ by cytosolic CA. (4) H⁺ acidifies cells and is extruded into the subepithelium via Na⁺/H⁺ exchanger 1 (NHE1). (5) H⁺ stimulates acid sensors such as transient receptor potential vanilloid 1 (TRPV1), followed by the release of calcitonin gene–related peptide (CGRP) and nitric oxide (NO), which increases blood flow. (6) H⁺ is carried by blood flow, which acidifies portal vein (PV) blood. (7) Concurrently, cyclooxygenase (COX) produces prostaglandin E₂ (PGE₂), which signals HCO₃⁻ and mucus secretion, further protecting the mucosa. (8) Cytoplasmic HCO₃⁻ generated from CO₂ and HCO₃⁻ delivered by increased blood flow, and then loaded via Na⁺:HCO₃⁻ cotransporter (NBC1), is secreted through an apical solute carrier family 26Ax (SLC26A) anion exchanger or cystic fibrosis transmembrane conductance regulator (CFTR) to the lumen. Note that the net movement of CO₂ is lumen→mucosa (absorption), whereas net HCO₃⁻ movement is mucosa→lumen (secretion). These simultaneous movements result in net H⁺ absorption, which is consistent with the function of the Jacobs-Stewart cycle. pH_i, intracellular pH.