FIGURE 4.

Membrane receptors on parietal and enterochromaffin-like (ECL) cells and intracellular signaling pathways that regulate gastric acid secretion. Stimulatory pathways are indicated in green, and inhibitory pathways are indicated with red lines. The parietal cell expresses G protein-coupled receptors (GPCRs) for acid secretagogues, including the muscarinic receptor (M3) for acetylcholine, the gastrin receptor (CCK2), and the histamine receptor (H2). M3 and CCK2 receptors are coupled to G protein G_q that activates phospholipase C (PLC), which leads to intracellular Ca²⁺ release to potentiate acid secretion. Binding of histamine to the H2 receptor activates adenylate cyclase (AC) to generate cAMP through G_s signal, which potently stimulates H⁺-K⁺-ATPase (H/K) activity via cAMP-dependent protein kinase (PKA). Histamine release from ECL cells is stimulated by a variety of receptors, including CCK2, PAC1, EP4, and the motilin receptors. Several receptors for inhibitors of gastric acid secretion are present on parietal cells including GLP-1R, NTS2, IP, EP3, CRF2, EGFR, and SST2 receptors. The inhibitory G protein (G_i) suppresses AC activities to inhibit cAMP-mediated secretory pathways. Additionally, nitric oxide (NO) inhibits acid secretion through the cGMP pathway. Angiotensin-like peptide receptor (APJ), activated by parietal cell-derived apelin, exerts both inhibitory and stimulatory effects. The H3 histamine receptor, expressed on ECL cells, contributes to negative feedback for histamine release.