Week 2: Acid production by the stomach Flashcards
Functions of acid production by the stomach
- Antimicrobial function (pH <2.0) (blood is usually 7.35 and stomach is about 1.8)
Cells that produce HCl
Parietal cells
Acid output vs time after food consumption
The chemical equation of acid production
CO2 + H2O -carbonic anhydrase-> HCO3- + H+ which lowers the pH
Then HCO3- is transported out of the cell and Cl- into the cell by an antiporter
H+ is transported into the lumen of the stomach and a K+ into the cell by an ATPase antiporter (K+ H+ ATPase antiporter)
Too much K+ could block the function of the K+ H+ ATPase antiporter so there is a K+ leak channel
Cl- is transported into the lumen and operates on a gradient from the parietal cell concentration gradient and charge driven due to the H+ in the lumen causing a positive charge in the lumen helping to drive the Cl- channel
Speed of carbonic anhydrase enzyme
convert 10^8 CO2 to HCO3- + H+ / second
gene to protein timeframe
~14 hrs
How does the parietal cell respond so quickly to a meal?
there are numerous vesicles that contain the K+H+ ATPase transporter so that way when food is eaten and the parietal cell is activated, these vesicles fuse to the lumen membrane of the parietal cell to allow for transport quickly after a meal instead of having to transcribe a new protein from DNA (would take ~14 hrs if proteins had to be transcribed from DNA)
What stimulates the parietal cell to start secreting HCl?
4 listed
- (don’t want this process to occur unless there is food present) so
- Vagus nerve stimulation (when food is sensed via cephalic phase of digestion)
- Also, gastrin stimulation from G cell secretion of gastrin into the blood to directly stimulate the parital cell (Gastric phase of digestion)
- Mechano receptors sensing stretching of stomach leading to further G cell activation and gastrin secretion
- Histamine secreted by ECL cells and sensed through the H2 receptor on the parietal anti-luminal membrane
Cephalic phase of digestion
when food is sensed salivary glands and vagus nerve stimulation
Pavlov experiment
sensing food leads to salivary production and vagal nerve stimulation (cephalic phase of digestion)
Enteroendocrine cells
3 listed
- G cell (open to dietary signals in the lumen)
- ECL cell (closed, completely closed off to the lumen by tissues and has no contact of sensing dietary components but it does sense gastrin)
- D cell (open type) recognizes rising concentrations of H+ in the lumen and secreted somatostatin into the blood and paracrine
What is the G cell responsible for?
sensing amino acids and peptides -> dietary source from lumanal surface receptors
leads to secretion of gastrin which enters the blood
Gastrin stimulates the parietal cell
Also mechanoreceptors in the lumen of the stomach sense when the stomach is stretched leading to further G cell activation
What is the gastric phase of digestion
gastrin stimulation from G cells sensing peptides and amino acids in the lumenal surface of the stomach and then secreting gastrin into the blood to directly stimulate the parital cell (Gastric phase of digestion)
Gastrin receptor name and location
CCK-B receptor (Cholecystokinin receptor) on parietal cells
How are G cells stimulated?
Amino acids and peptides
Also mechanoreceptors in the lumen of the stomach sense when the stomach is stretched leading to further G cell activation
Leads to Gastrin secretion into the blood
What is an ECL cell?
Enterochromaffin-like cell
Function of ECL cells
- Closed off to the lumen and does not sense any dietary components as it is completely closed off to the lumen by tissue
- However, it does respond to gastrin and vagal stimulation
- Stimulation leads to Histamine production and secretion
- Histamine acts similarly to gastrin and stimulates the parietal cell through the H2 histamine receptor
Describe potentiation
- stimulatory factors are additive or more than additive to one another in a synergistic manner
- Gastrin causes stimulation of parietal cells, however, histamine + gastrin leads to a greater stimulation than just one of them so lower concentrations of both gastrin and histamine can produce greater stimulation than just one alone.
- Gastrin is stronger than histamine in stimulating parietal cells
What is cimetidine?
Rx which is an H2 antagonist which prevents the binding of histamine on acid secretion
Since histamine will be blunted gastrin will be the only stimulation on parietal cells on acid secretion outside of vagal stimulation
Cimetidine effectively blocks the mechanism that is potentiation
How many acid secretion stimulatory factors are there and what phase of digestion are they in?
listed
ACh by vagus nerve (Cephalic phase of digestion) ^ Ca2+ and acts as a second messenger for acid production
CCK-b gastrin receptor (gastric phase of digestion) ^ intracellular [Ca2+] and acts as a second messenger for acid production
H2 histamine receptor (gastric phase of digestion) stimulates adenylate cyclase ^cAMP
Ca2+ effect on parietal cells
Ca2+ stimulates the fusion of K+H+ ATPase antiporter vesicles concentrated near the lumen membrane, to the luminal membrane
cAMP effect on parietal cells
What is Omeprazole?
K+H+ ATPase antiporter inhibitor
Is the drug of choice for inhibiting acid production because it is an irreversible inhibitor and binds covalently to the transporter (nondissociable)
So the parietal cell has to degrade the transporter in proteasomes and would need to produce more transporter through de novo synthesis
Omeprazole becomes activated by low pH and the drug is inactive at neutral pH
patient takes the omeprazole orally and is absorbed into the blood (pH 7.35) transported into the parietal cell and becomes localized to the vesicles bound to the transporter, when the vesicles fuse to the lumen surface the drug then activates forming the covalent link with the K+H+ ATPase antiporter and shuts down the pump irreversibly
D cell description and function
- D cell (open type enteroendocrine cell) recognizes rising concentrations of H+ in the lumen (low pH) and secreted somatostatin into the blood and paracrine effects to stimulate the local environment and bind to the somatostatin receptor on ECL cells in a (paracrine fashion)
- so now that the ECL cell is inhibited from secreting more histamine
- Somatostatin also binds to G cells on a somatostatin receptor and inhibits the secretion of Gastrin (endocrine fashion)
- Overall, this prevents gastrin and histamine stimulation of parietal cells so that K+H+ ATPase antiporter no longer is stimulated to fuse to the luminal membrane and instead, the K+H+ ATPase antiporters are retrieved via invagination and remains stored in a vesicle and its function is now prevented
- Result is pH begans to rise
What activates G cells?
- Senses Amino Acids and peptides in the lumen of the stomach
- Further activated by mechanoreceptors in the stomach that sense stretching due to food
- Further activated by histamine receptors from ECL cells
Function of G cells
secrete gastrin to activate parietal cells production and secretion of HCl into the lumen of the stomach
What is the gastrin receptor?
CCK-b
What is CCK-b?
- Cholecystokinen B
- Receptor for gastrin
CCK-b mechansim
Binds gastrin and raises intracellular Ca2+
Parietal cell Activation signals
3 listed
- Vagal stimulation (ACh receptor) (cephalic phase)
- CCK-b (Gastrin receptor) (Gastric phase)
- H2 (Histamine receptor) (gastric phase)
Parietal cell second messenger
- Ca2+ Increasing levels result in greater parietal cell activation
- cAMP through adenylate cyclase in response to the histamine receptor
Parietal cell vagal stimulation pathway
- Seeing or smelling food (cephalic phase of digestion)
- ACh receptor activated on parietal cells
- Increases intracellular Ca2+
- Ca2+ causes vesicles containing H+/K+ ATPase antiporters to fuse with the plasma membrane to decrease the pH of the lumen by pumping protons into the lumen and bringing K+ into the cell
- K+ has a leak channel to prevent K+ build-up within parietal cells
Describe Gastrin secretion inhibition
- D-cells sense increasing H+ concentration and once reaching a threshold of binding affinity, the D-cell then is stimulated to secrete Somatostatin
- Somatostatin (hormone responsible for inhibition) enters the blood also has paracrine effects and binds to the Somatostatin receptor on ECL-cells in a paracrine fashion and inhibits histamine secretion
- In an endocrine fashion, Somatostatin binds to G-cells on Somatostatin receptors and inhibits the secretion of Gastrin
- Without Gastrin and Histamine stimulation, the parietal cell’s Ca2+ and cAMP decrease, the K+/H+ ATPase is invaginated back into vesicles and protons can no longer be pumped into the lumen and pH begins to rise
