Overview Gastric secretion cells of gastric mucosa secrete gastric juice composed of hydrochloric acid (HCl), pepsinogen, intrinsic factor (IF), and mucus HCl and pepsinogen initiate protein digestion IF is required for vitamin B12 absorption in ileum mucus protects gastric mucosa from corrosive action of HCl and lubricates gastric contents Gastric Glands Oxyntic glands body of stomach contains oxyntic glands oxyntic glands empty secretory products via ducts into lumen of stomach opening of ducts are called gastric pits oxyntic glands contain parietal cells and chief cells parietal cells secrete HCl and IF into oxyntic ducts chief cells secrete pepsinogen into oxyntic ducts Pyloric glands antrum of stomach contains pyloric glands pyloric glands empty secretory products via ducts into lumen of stomach opening of ducts are called gastric pits pyloric glands contain G cells and mucosal neck cells G cells secrete gastrin into systemic circulation, not into pyloric ducts mucosal neck cells secrete mucus and HCO3- into pyloric ducts mucus forms a gel-like protective barrier between gastric mucosal cells and gastric lumen protects gastric mucosal cells against acid (HCl) and digestive enzymes (pepsin) HCO3- embeds in mucosal gel-like protective barrier neutralizes any HCl that may penetrate mucosal layer inactivates any pepsin that may penetrate mucosal layer Gastric Parietal Cell Parietal cell polarity apical membrane contains H+-K+ ATPase and Cl- channels basolateral membrane contains Na+-K+ ATPase and Cl-/HCO3- exchanger Parietal cell secretion parietal cells secrete HCl and IF into oxyntic ducts that empty into lumen of stomach HCl acidifies gastric contents 1 ≤ pH ≤ 2 low pH converts inactive pepsinogen zymogen to active pepsin enzyme pepsin is a protease that initiates protein digestion Mechanism of HCl secretion aerobic metabolism of gastric parietal cell produces CO2 intracellularly, CO2 combines with H2O to form H2CO3, which dissociates into H+ and HCO3- CO2 + H2O → H2CO3 → H+ + HCO3- carbonic anhydrase catalyzes hydration of CO2 at apical membrane, H+ is secreted into lumen of stomach via H+-K+ ATPase H+ secretion inhibited by omeprazole, a proton pump inhibitor and an antacid at apical membrane, Cl- "follows" H+ and is secreted into lumen of stomach via Cl- channels at basolateral membrane, HCO3- is absorbed from cell into bloodstream via Cl-/HCO3-exchanger HCO3- moves out of cell and into bloodstream HCO3- is responsible for "alkaline tide" (high pH) that is observed in gastric venous blood following a meal eventually, HCO3- is secreted back into gastrointestinal tract in pancreatic secretions Cl- moves out of bloodstream and into cell Activation of HCl secretion stimuli smelling, tasting, and conditioned reflexes in anticipation of food via vagal stimulation direct and indirect pathways of stimulation distension of stomach via vagal stimulation direct and indirect pathways of stimulation presence of breakdown products of protein (small peptides and amino acids) via stimulation of gastric G cells to secrete gastrin phenylalanine and tryptophan are most potent stimuli for gastric secretion vagal stimulation direct pathway vagus nerve innervates gastric parietal cells at synapse, ACh is released and binds muscarinic M3 receptors coupled to Gq proteins ↑ ACh → (+) M3 receptors → (+) Gq proteins → (+) PLC → ↑ DAG and IP3 IP3 releases Ca2+ from intracellular stores DAG and Ca2+ → (+) PKC → (+) H+-K+ ATPase → ↑ HCl secretion via gastric parietal cells indirect pathway vagus nerve innervates gastric G cells at synapse, gastrin-releasing peptide (GRP) is released GRP → ↑ gastrin secretion via gastric G cells atropine atropine inhibits HCl secretion via gastric parietal cells atropine is a cholinergic muscarinic antagonist atropine blocks muscarinic M3 receptors on gastric parietal cells blocks ACh-mediated, direct pathway of HCl secretion atropine does not inhibit HCl secretion via gastric parietal cells completely atropine does not block GRP-mediated, indirect pathway of HCl secretion histamine histamine is released from enterochromaffin-like (ECL) cells in gastric mucosa histamine diffuses to nearby gastric parietal cells paracrine mechanism of delivery histamine binds H2 receptors coupled to Gs proteins on gastric parietal cells histamine → (+) H2 receptors → (+) Gs proteins → (+) adenylyl cyclase → ↑ cAMP ↑ cAMP → (+) PKA → (+) H+-K+ ATPase → ↑ HCl secretion via gastric parietal cells HCl secretion inhibited by cimetidine, a H2 receptor inhibitor and an antacid gastrin gastrin is released from G cells of antrum of stomach into systemic circulation gastrin is not released into pyloric ducts that empty into lumen of stomach gastrin is delivered back to stomach via systemic circulation endocrine mechanism of delivery gastrin stimulates HCl secretion via gastric parietal cells by 2 mechanisms gastrin binds CCKB receptors coupled to Gq proteins on gastric parietal cells gastrin → (+) CCKB receptors → (+) Gq proteins → (+) PLC → ↑ DAG and IP3 IP3 releases Ca2+ from intracellular stores DAG and Ca2+ → (+) PKC → (+) H+-K+ ATPase → ↑ HCl secretion via gastric parietal cells gastrin binds CCKB receptors on ECL cells gastrin → (+) CCKB receptors → ↑ histamine secretion → ↑ HCl secretion via gastric parietal cells gastrin stimulates HCl secretion primarily by acting on ECL cells Zollinger-Ellison syndrome increased HCl secretion via gastric parietal cells caused by a gastrin-secreting tumor (gastroma) increased HCl (H+) secretion may cause duodenal ulcers increased acidification inactivates pancreatic lipase, an enzyme necessary for lipid digestion lipids are not adequately digested nor absorbed lipid excretion in feces (steatorrhea) Inhibition of HCl secretion occurs when chyme is propelled along gastrointestinal tract from stomach to duodenum of small intestine HCl is no longer required to activate pepsinogen zymogen to active pepsin enzyme ↓ pH gastric contents acidify (pH lowers) when chyme is propelled along gastrointestinal tract from stomach to duodenum of small intestine food acts as a buffer for H+ in stomach food in stomach as gastric parietal cells secrete HCl, food buffers H+ and gastric contents acidify only slightly food in duodenum buffering capacity in stomach is reduced as gastric parietal cells secrete HCl, gastric contents further acidify pH < 1.5 initiates a negative feedback mechanism by inhibiting gastrin secretion via G cells somatostatin somatostatin is secreted by D cells of gastric mucosa somatostatin binds receptors coupled to Gi proteins on gastric parietal cells somatostatin → (+) receptors → (+) Gi proteins → (-) adenylyl cyclase → ↓cAMP ↓ cAMP → (-) PKA → (-) H+-K+ ATPase → ↓ HCl secretion via gastric parietal cells somatostatin antagonizes stimulatory effect of histamine on HCl secretion prostaglandins prostaglandins bind receptors coupled to Gi proteins on gastric parietal cells prostaglandins → (+) receptors → (+) Gi proteins → (-) adenylyl cyclase → ↓cAMP ↓ cAMP → (-) PKA → (-) H+-K+ ATPase → ↓ HCl secretion via gastric parietal cells prostaglandins antagonizes stimulatory effect of histamine on HCl secretion IF secretion IF is required for vitamin B12 absorption in ileum IF is only essential secretion of stomach IF deficiency causes pernicious anemia Gastric Chief Cell Chief cell function chief cells secrete pepsinogen into oxyntic ducts that empty into lumen of stomach pepsinogen is a zymogen (inactive enzyme) that must be activated through cleavage increased concentration of H+ in gastric contents provides the low pH signal low pH converts inactive pepsinogen zymogen to active pepsin enzyme pepsin is a protease that initiates protein digestion activation of pepsinogen secretion stimuli vagal stimulation → ↑ pepsinogen secretion via chief cells ↑ H+ → ↑ pepsinogen secretion via chief cells