Gastric acid secretion is the final product of a complex signaling cascade in gastric parietal cells, and understanding this physiology is essential for rational acid suppression therapy. Parietal cells in the gastric fundus and body secrete hydrochloric acid (HCl) via the hydrogen-potassium ATPase (H+/K+-ATPase, the proton pump) located on their apical (luminal) surface. Three primary stimuli activate parietal cells: acetylcholine (vagal parasympathetic stimulation via M3 muscarinic receptors), gastrin (released from G-cells in the antrum in response to meal-related gastric distension and protein), and histamine (released from enterochromaffin-like cells and binding to H2 receptors on parietal cells). Histamine is the final common paracrine mediator — gastrin and acetylcholine both stimulate histamine release from ECL cells, making the H2 receptor a convergence point for acid secretion stimulation. Proton pump inhibitors (PPIs) irreversibly bind to the active (acid-secreting) conformation of the H+/K+-ATPase, blocking the final common pathway of acid secretion regardless of the upstream stimulus. Because PPIs only inhibit actively secreting pumps, they must be taken 30-60 minutes before a meal when meal anticipation stimulates pump translocation to the apical membrane. Since proton...