Updated: 10/29/2018

Gastric Secretion

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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
      • smellingtasting, 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

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