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
5;260(25):13681-4.
2.- Shull GE, Lingrel JB. (1986) Molecular cloning of the rat stomach (H+ + K+)ATPase. J Biol Chem. 1986 Dec 25;261(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.
Keywords:
Chief cells, Parietal cells, Goblet cells
Tubulovesicular network
Cymetidine, Omeprazole
H+/K+ ATPase
Carbonic Anhydrase
Chloride bicarbonate exchanger
Na+/H+ exchanger
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.
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.
Types of Glands
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.
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.
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 3.5also can catalyze the activation of pepsinogens.
Morphological transformation of the parietal cell
Resting
Stimulated
apical
apical
basal
basal
The Ussing chamber
Can be used to study sodium transport by frog skin!
Experimental demonstration of the change in morphology
of the gastric gland upon stimulation
Ra
Ca
Rb
Cb
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.
Morphological transformation of the parietal cell
Resting
Stimulated
apical
apical
basal
basal
Discovery of the H+/K+ ATPase
Vesicular membrane potential for various K+ gradients of K+in/K+out. 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 Clgradients. 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.
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]
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.
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.
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.
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.
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.
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 Clby HCO-3 in order to neutralize the acid from the stomach and allow the digestive
enzymes to work.