1.-Architecture%20of%20the%20gastric%20gland

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Gastric Secretion
1.-Architecture of the gastric gland
2.- The unique H/K ATPase
3.-Acid secretion homeostasis
Readings 1.-Wallmark B, Larsson H, Humble L.
(1985) The relationship between gastric acid
secretion and gastric H,K-ATPase activity. J
Biol Chem. 1985 Nov 5260(25)13681-4. 2.- Shull
GE, Lingrel JB. (1986) Molecular cloning of the
rat stomach (H K)-ATPase. J Biol Chem. 1986
Dec 25261(36)16788-91. 3.-Anthony
M. Paradiso, Roger Y. Tsien  Terry E. Machen
(1987) Digital image processing of intracellular
pH in gastric oxyntic and chief cells.
Nature 325, 447 450.
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Keywords Chief cells, Parietal cells, Goblet
cells Tubulovesicular network Cymetidine,
Omeprazole H/K ATPase Carbonic
Anhydrase Chloride bicarbonate exchanger Na/H
exchanger
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The simplest possible gland is a single cell or
cluster of cells in an epithelium, secreting onto
the surface (i.e., the mucus secreting goblet
cell).
Features common to all epithelia a continuous
sheet of cells so that nothing can go in or out
of the body without being monitored. Cells show
polarity, where the morphology and properties of
the membrane facing the inside or the outside of
the body, are different. Extensive cell-to-cell
contacts called tight junctions (zonula
occludens) provide the means of holding the cells
together and eliminate the extracellular space
(so that nothing can leak between the cells).
Finally, in an epithelia, one can always find a
basal lamina a mesh of collagen fibers over
which the epithelial cells rests.
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This gland consists of an invaginated epithelium
of secretory cells lining a blind cavity called
acinus. The acinus connects to a small duct that,
in turn, along with other acini (not shown),
connects to a larger duct that empties at some
point of the digestive canal. The epithelial
cells that form the acinus (acinar cells) have a
characteristic pyramidal shape. The acinar cells
have an apical membrane, which faces the lumen
(the lumen is the cavity of any hollow organ or
tube) and is the secretory surface of the cell.
We also have a basal membrane facing the basal
lamina and is the place where water and solutes
are exchanged between the plasma and the acinar
cells. The various substances secreted by the
acinar cells comprise the primary secretions,
which are subsequently modified by secretions of
the duct cells, this is called secondary
modifications.
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Types of Glands
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pH-Log H
The gastric gland generates a fluid mixture
composed of mucus, pepsinogen and an electrolytic
solution composed of H (145 mM), Cl- (155 mM)
and K (10 mM). Note that the pH of the gastric
juice is less than 1 this means that there is a
H gradient of about six orders of magnitude
between the plasma and the lumen of the gastric
gland.
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Two other cell types coexist with the parietal
and gastric mast cells. These are the chief cells
which secrete pepsinogen (a precursor of pepsin)
and the ubiquitous goblet cell that secretes
mucus, also by exocytosis. The morphology of
these cells is shown below. A striking feature of
the goblet cells is that their secretory granules
are so tightly packed that their membranes touch
over extensive regions.
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Activation of the pepsinogens to pepsins. At pH
values from 5 to 3, pepsinogens spontaneously
activate to pepsins by the removal of an
N-terminal "activation peptide." This spontaneous
activation is even faster at pH values that are
below 3. The newly formed pepsins
themselves-which are active only at pH values
below 3.5-also can catalyze the activation of
pepsinogens.
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Morphological transformation of the parietal cell
Resting
Stimulated
apical
apical
basal
basal
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The Ussing chamber
Can be used to study sodium transport by frog
skin!
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Experimental demonstration of the change in
morphology of the gastric gland upon stimulation
Ra
Rb
Cb
Ca
Equivalent circuit for a gastric gland mounted on
a Ussing chamber. Ra and Rb represent the apical
and basal membrane resistance, Ca and Cb are the
apical and basal membrane capacitances,
respectively. Rs represents the series resistance
associated with the bathing saline. Upon
stimulation with histamine, Ra decreased by a
factor of 5 and Ca increased 10 times whereas Rb
and Cb remained constant. These results are in
good agreement with a large increase in apical
surface area upon stimulation.
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Morphological transformation of the parietal cell
Resting
Stimulated
apical
apical
basal
basal
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Discovery of the H/K ATPase
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Vesicular membrane potential for various K
gradients of Kin/Kout. Both the vesicles from
resting (a) and stimulated (b) gastric mucosa
show a similar dependence of the vesicular
membrane potential, implying that both types of
vesicles are equally permeable to K. (c) plots
the vesicular potential versus the log of the Cl-
concentration ratio and shows that only the
vesicles from the stimulated gastric gland,
respond to Cl- gradients. These results imply
that there is a new Cl- conductance activated in
the stimulated vesicular fraction. We conclude
that there are separate K and Cl- pathways and
that stimulation of the gland leads to the
activation of a Cl- conductance in the secretory
membrane of the parietal cell.
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In 1985, B. Wallmark used the new drug
omeprazole to demonstrate that the H/K enzyme
was responsible for acid secretion in the
gastric gland.
omeprazole
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Acid secretion by parietal cells. When the
parietal cell is stimulated, H-K pumps (fueled by
ATP hydrolysis) extrude H into the lumen of the
gastric gland in exchange for K. The K recycles
back into the lumen via K channels. Cl exits
through channels in the luminal membrane,
completing the net process of HCl secretion. The
H needed by the H-K pump is provided by the
entry of CO2 and H2O, which are converted to H
and HCO3 by carbonic anhydrase. The HCO3 exits
across the basolateral membrane via the Cl-HCO3
exchanger. ATP, adenosine triphosphate.
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The direct and indirect actions of the three acid
secretagogues acetylcholine, gastrin, and
histamine. ACh, acetylcholine CCKb,
cholecystokinin B ECL, enterochromaffin-like
ENS, enteric nervous system.
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Diffusion barrier in the surface of the gastric
mucosa. A, The mucus secreted by the surface
cells serves two functions. First, it acts as a
diffusion barrier for H and also pepsins.
Second, the mucus layer traps a relatively
alkaline solution of HCO3. This HCO3 titrates
any H that diffuses into the gel layer from the
stomach lumen. The alkaline layer also
inactivates any pepsin that penetrates into the
mucus. B, If H penetrates into the gastric
epithelium, it damages mast cells, which release
histamine and other agents, setting up an
inflammatory response. If the insult is mild, the
ensuing increase in blood flow can promote the
production of both mucus and HCO3 by the mucus
cells. If the insult is more severe, the
inflammatory response leads to a decrease in
blood flow and thus to cell injury.
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Receptors and signal-transduction pathways in the
parietal cell. The parietal cell has separate
receptors for three acid secretagogues.
Acetylcholine (ACh) and gastrin each bind to
specific receptors (M3 and CCKb, respectively)
that are coupled to the G protein Gaq. The result
is activation of phospholipase C (PLC), which
ultimately leads to the activation of protein
kinase C (PKC) and the release of Ca2. The
histamine binds to an H2 receptor, coupled
through Gas to adenylyl cyclase (AC). The result
is production of cAMP and activation of PKA. Two
inhibitors of acid secretion also act directly on
the parietal cell. Somatostatin and
prostaglandins bind to separate receptors that
are linked to Gai. These agents thus oppose the
actions of histamine. cAMP, cyclic adenosine
monophosphate CCKb, cholecystokinin B DAG,
diacylglycerol ER, endoplasmic reticulum PIP2,
phosphatidyl inositol 4,5-biphosphate.
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The pulse-chase experiments of Palade defined the
secretory pathway
Movement of newly synthesized proteins through
the secretory pathway. The cell model at the top
illustrates the vectoral movement of nascent
proteins through the compartments of the
secretory pathway. The four records in the graph
show the time course of secretory proteins moving
through these compartments. To radioactively
label newly synthesized proteins, George Palade
briefly pulsed the pancreatic acinar cells with
3H-labeled amino acids. At specific times after
the pulse, tissues were fixed, and the
distribution of the radioactive amino acid was
determined using autoradiography. Each of the
four records shows the number of radiographic
grains-as a fraction of all of the grains-found
in each compartment at various times after the
pulse. ER, endoplasmic reticulum.
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Flow dependence of the electrolyte composition of
pancreatic fluid. Note that as the rate at which
fluids flow out of the pancreas increases, the
composition changes replacing Cl- by HCO-3 in
order to neutralize the acid from the stomach and
allow the digestive enzymes to work.
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