Comprehensive Physiology Wiley Online Library

Cell Biology of Hydrochloric Acid Secretion

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Functional Morphology of The Oxyntic Cell
1.1 General Structure
1.2 Ultrastructure of Oxyntic Cells
1.3 Membrane Turnover and Recycling
1.4 Cytoskeleton of Oxyntic Cell
2 Receptors Regulating Oxyntic Cell Function
2.1 Techniques for Studying Gastric Glands and Cell Preparations
2.2 Studies of Receptor Specificity
2.3 Receptors on Nonoxyntic Cells
3 Cellular Basis of Hydrochloric Acid Secretion
3.1 H+‐K+‐ATPase: the Primary H+‐Pump Enzyme
3.2 Membrane Changes Associated With Hydrochloric Acid Secretion
3.3 Hydrochloric Acid Transport at the Apical Cell Membrane
3.4 Transport at the Basolateral Membrane
3.5 Oxyntic Cell Transport Model
4 Cell‐Activation Mechanisms
4.1 Oxyntic Cell Activation by Cyclic AMP
4.2 Prostaglandin Inhibition of Oxyntic Cell Function
4.3 Oxyntic Cell Activation by Calcium‐Dependent Mechanisms
Figure 1. Figure 1.

Isolated gastric gland. Glands were isolated from rabbit fundic mucosa, stimulated with Bt2cAMP, and subsequently fixed and stained with a fluorescent‐labeled probe for filamentous actin (phallacidin) . The glands appear as a tube of cells, with the oxyntic cells (ox) tending to bulge outward from the wall of the gland. Under fluorescence microscopy the distribution of actin microfilaments provides additional detail of cytoskeletal organization. Oxyntic cells are well stained; distribution of the actin stain is localized to microvilli in the expanded secretory canaliculi of stimulated oxyntic cells. No stain is visible within the cytoplasm of chief cells (cc), the other major cell type within the gland. Thin deposits of stain define the gland lumen (lu); this pattern is consistent with actin microfilaments within luminal microvilli of both cell types. Bar, 20 μm.

Figure 2. Figure 2.

Resting (nonsecreting) oxyntic cells from piglet gastric mucosa. A: low‐power view showing oxyntic cells in a section cut across the gastric gland. Lumen (L) of the gland is visible, as well as intercellular spaces (IS), basolateral folds (BF), and a capillary (cap) on the interglandular space. Secretory canaliculi (C) extend from the gland lumen into the cell and contain short stubby microvilli. The cytoplasm of the oxyntic cell, especially the apical portion, contains numerous tubular and vesicular membranous profiles of the “tubulovesicles” (TV), and large mitochondria (M) are readily apparent. Bar, 1 μm. B: high‐power view of apical microvilli showing organization of microfilaments (MF) in longitudinal as well as cross section (inset). Tubulovesicles can also be seen beneath the apical plasma membrane. Bars, 0.1 μm.

A from Forte and Machen a)
Figure 3. Figure 3.

Maximally stimulated oxyntic cells from piglet gastric mucosa. A: secretory canaliculi (C) are filled with long microvilli, greatly expanding the apical surface area. Only a relatively few tubulovesicles are left within the cytoplasm. Bar, 1 μm. B: high‐power view of expanded apical surface in which microfilaments (MF) and microtubules (MT) can be seen. Bar, 0.1 μm.

A from Forte and Machen a)
Figure 4. Figure 4.

Model for receptor regulation of canine parietal cell function. This revised model depicts pharmacologically specific muscarinic, histamine, and gastrin receptors on the canine parietal cell. Respectively, these 3 receptors can be selectively blocked by atropine (A), H2 histamine antagonists (H2B), and proglumide . Histamine activates adenylate cyclase, acting at a stimulatory receptor (R8), which in turn activates the stimulatory GTP‐binding protein G8. There also appears to be an inhibitory receptor (Ri) for PGE2 that is linked to the catalytic subunit (C) of adenylate cyclase via the inhibitory GTP‐binding protein Gi. Acetylcholine and gastrin act in a Ca2+‐dependent fashion, although specific details regarding mechanisms increasing cytosolic Ca2+ remain uncertain.

Figure 5. Figure 5.

Models of H+ pumping and ion transport in gastric membrane vesicles. A: pump‐leak model for ion transport in isolated microsomal vesicles from resting gastric mucosa. Microsomal model consists of an ATP‐driven H+‐K+ exchange pump and passive leak pathways for the principal ions, H+, K+, and Cl. J, ion flux, with superscripts designating the pump flux (P) or leak pathway (L). B: schematic representation of the mechanism of HCl accumulation in vesicles isolated from apical plasma membrane of stimulated oxyntic cells (stimulation‐associated vesicles). These vesicles are significantly different from microsomes by virtue of ionic conductances for K+ (Gk) and CI (Gcl), which provide pathways for rapid entry of KCl. As for the microsomal vesicles, the ATP‐driven H+‐K+ exchange pump provides the force to accumulate intravesicular HCl.

Figure 6. Figure 6.

H+ uptake in gastric microsomal vesicles is dependent on Cl concentration and K+ ionophores. H+ uptake was monitored by the acridine orange fluorescence‐quenching method. Addition of ATP to a suspension of microsomal vesicles resulted in a small uptake of H+ that was accelerated by the subsequent addition of the K+ ionophore valinomycin (val). K+ concentration was constant at 150 mM in all cases; Cl concentration was varied as shown; isethionate was used as the balance anion. The rate of H+ uptake was greatly enhanced by increasing the concentration of the permeant anion, Cl. All H+ gradients were abolished by the H+‐K+ exchange ionophore nigericin (nig).

From Lee and Forte
Figure 7. Figure 7.

Comparison of ATP‐driven H+ uptake in gastric microsomal vesicles and stimulation‐associated vesicles. As in Figure , H+ uptake was monitored by the acridine fluorescence‐quenching method. At the indicated time, gastric microsomes (g. mic.) were added to uptake medium consisting of 150 mM KCl, 0.5 mM MgATP, and 5 μM acridine orange, with the result of very little H+ uptake. Addition of valinomycin (val) increased K+ permeability and K+ influx, also resulting in greatly increased H+ uptake and ATP turnover. When stimulation‐associated vesicles (s.a. ves.) were added to the same medium there was an immediate rapid uptake of H+ that was not increased by valinomycin, indicating that a pathway for rapid K+ entry was present in these apical membrane vesicles from stimulated oxyntic cells.

Figure 8. Figure 8.

Schematic representation of the oxyntic cell transport in the transformation from rest to activate HCl secretion. In the resting cell, tubulovesicles contain H+‐K+‐ATPase, but because of low membrane permeability to K+ (and Cl) there is very little H+ accumulation and virtually no ATP turnover. Cell activation brings about a fusion of tubulovesicles with the apical plasma membrane, transferring the H+‐K+‐ATPase to that surface. In addition the participation of conductive pathways (possibly activated?) for K+ and Cl movement provides the means for KCl movement into the secretory canaliculi. The H+‐K+ exchange pump recycles K+ back into the cytoplasm with the net effect of HCl transfer and ATP turnover. Water flux into the canaliculus is osmotically driven by the net solute flux.

Figure 9. Figure 9.

Transport model of gastric oxyntic cell. Apical membrane contains H+‐K+ pump and conductive pathways for K+ and Cl. Basolateral membrane contains N+‐K+ pump, a K+ conductance, and separate Na+‐H+ and Cl‐HCO3 exchange (ex) mechanisms.

From Reenstra et al.
Figure 10. Figure 10.

Pertussis toxin attenuation of enprostil inhibition of histamine‐stimulated [14C]aminopyrine ([14C]‐AP) accumulation. Enriched parietal cells were cultured overnight in the absence (A) or presence (B) of 300 ng/ml of pertussis toxin. [14C]aminopyrine accumulation was then studied in response to the indicated concentrations of histamine alone (open squares) or in the presence of 10 nM (closed diamonds) or 1 μM enprostil (open triangles). Data (means ± SE from 5 separate cell preparations) were expressed as percentage of the maximal response to histamine. This maximal value over basal in control cells was a [14C]aminopyrine ratio of 21.3 ± 3.3, whereas in the cells treated with pertussis toxin the maximal response to histamine was 19.2 ± 4.6. IBMX, isobutylmethylxanthine.



Figure 1.

Isolated gastric gland. Glands were isolated from rabbit fundic mucosa, stimulated with Bt2cAMP, and subsequently fixed and stained with a fluorescent‐labeled probe for filamentous actin (phallacidin) . The glands appear as a tube of cells, with the oxyntic cells (ox) tending to bulge outward from the wall of the gland. Under fluorescence microscopy the distribution of actin microfilaments provides additional detail of cytoskeletal organization. Oxyntic cells are well stained; distribution of the actin stain is localized to microvilli in the expanded secretory canaliculi of stimulated oxyntic cells. No stain is visible within the cytoplasm of chief cells (cc), the other major cell type within the gland. Thin deposits of stain define the gland lumen (lu); this pattern is consistent with actin microfilaments within luminal microvilli of both cell types. Bar, 20 μm.



Figure 2.

Resting (nonsecreting) oxyntic cells from piglet gastric mucosa. A: low‐power view showing oxyntic cells in a section cut across the gastric gland. Lumen (L) of the gland is visible, as well as intercellular spaces (IS), basolateral folds (BF), and a capillary (cap) on the interglandular space. Secretory canaliculi (C) extend from the gland lumen into the cell and contain short stubby microvilli. The cytoplasm of the oxyntic cell, especially the apical portion, contains numerous tubular and vesicular membranous profiles of the “tubulovesicles” (TV), and large mitochondria (M) are readily apparent. Bar, 1 μm. B: high‐power view of apical microvilli showing organization of microfilaments (MF) in longitudinal as well as cross section (inset). Tubulovesicles can also be seen beneath the apical plasma membrane. Bars, 0.1 μm.

A from Forte and Machen a)


Figure 3.

Maximally stimulated oxyntic cells from piglet gastric mucosa. A: secretory canaliculi (C) are filled with long microvilli, greatly expanding the apical surface area. Only a relatively few tubulovesicles are left within the cytoplasm. Bar, 1 μm. B: high‐power view of expanded apical surface in which microfilaments (MF) and microtubules (MT) can be seen. Bar, 0.1 μm.

A from Forte and Machen a)


Figure 4.

Model for receptor regulation of canine parietal cell function. This revised model depicts pharmacologically specific muscarinic, histamine, and gastrin receptors on the canine parietal cell. Respectively, these 3 receptors can be selectively blocked by atropine (A), H2 histamine antagonists (H2B), and proglumide . Histamine activates adenylate cyclase, acting at a stimulatory receptor (R8), which in turn activates the stimulatory GTP‐binding protein G8. There also appears to be an inhibitory receptor (Ri) for PGE2 that is linked to the catalytic subunit (C) of adenylate cyclase via the inhibitory GTP‐binding protein Gi. Acetylcholine and gastrin act in a Ca2+‐dependent fashion, although specific details regarding mechanisms increasing cytosolic Ca2+ remain uncertain.



Figure 5.

Models of H+ pumping and ion transport in gastric membrane vesicles. A: pump‐leak model for ion transport in isolated microsomal vesicles from resting gastric mucosa. Microsomal model consists of an ATP‐driven H+‐K+ exchange pump and passive leak pathways for the principal ions, H+, K+, and Cl. J, ion flux, with superscripts designating the pump flux (P) or leak pathway (L). B: schematic representation of the mechanism of HCl accumulation in vesicles isolated from apical plasma membrane of stimulated oxyntic cells (stimulation‐associated vesicles). These vesicles are significantly different from microsomes by virtue of ionic conductances for K+ (Gk) and CI (Gcl), which provide pathways for rapid entry of KCl. As for the microsomal vesicles, the ATP‐driven H+‐K+ exchange pump provides the force to accumulate intravesicular HCl.



Figure 6.

H+ uptake in gastric microsomal vesicles is dependent on Cl concentration and K+ ionophores. H+ uptake was monitored by the acridine orange fluorescence‐quenching method. Addition of ATP to a suspension of microsomal vesicles resulted in a small uptake of H+ that was accelerated by the subsequent addition of the K+ ionophore valinomycin (val). K+ concentration was constant at 150 mM in all cases; Cl concentration was varied as shown; isethionate was used as the balance anion. The rate of H+ uptake was greatly enhanced by increasing the concentration of the permeant anion, Cl. All H+ gradients were abolished by the H+‐K+ exchange ionophore nigericin (nig).

From Lee and Forte


Figure 7.

Comparison of ATP‐driven H+ uptake in gastric microsomal vesicles and stimulation‐associated vesicles. As in Figure , H+ uptake was monitored by the acridine fluorescence‐quenching method. At the indicated time, gastric microsomes (g. mic.) were added to uptake medium consisting of 150 mM KCl, 0.5 mM MgATP, and 5 μM acridine orange, with the result of very little H+ uptake. Addition of valinomycin (val) increased K+ permeability and K+ influx, also resulting in greatly increased H+ uptake and ATP turnover. When stimulation‐associated vesicles (s.a. ves.) were added to the same medium there was an immediate rapid uptake of H+ that was not increased by valinomycin, indicating that a pathway for rapid K+ entry was present in these apical membrane vesicles from stimulated oxyntic cells.



Figure 8.

Schematic representation of the oxyntic cell transport in the transformation from rest to activate HCl secretion. In the resting cell, tubulovesicles contain H+‐K+‐ATPase, but because of low membrane permeability to K+ (and Cl) there is very little H+ accumulation and virtually no ATP turnover. Cell activation brings about a fusion of tubulovesicles with the apical plasma membrane, transferring the H+‐K+‐ATPase to that surface. In addition the participation of conductive pathways (possibly activated?) for K+ and Cl movement provides the means for KCl movement into the secretory canaliculi. The H+‐K+ exchange pump recycles K+ back into the cytoplasm with the net effect of HCl transfer and ATP turnover. Water flux into the canaliculus is osmotically driven by the net solute flux.



Figure 9.

Transport model of gastric oxyntic cell. Apical membrane contains H+‐K+ pump and conductive pathways for K+ and Cl. Basolateral membrane contains N+‐K+ pump, a K+ conductance, and separate Na+‐H+ and Cl‐HCO3 exchange (ex) mechanisms.

From Reenstra et al.


Figure 10.

Pertussis toxin attenuation of enprostil inhibition of histamine‐stimulated [14C]aminopyrine ([14C]‐AP) accumulation. Enriched parietal cells were cultured overnight in the absence (A) or presence (B) of 300 ng/ml of pertussis toxin. [14C]aminopyrine accumulation was then studied in response to the indicated concentrations of histamine alone (open squares) or in the presence of 10 nM (closed diamonds) or 1 μM enprostil (open triangles). Data (means ± SE from 5 separate cell preparations) were expressed as percentage of the maximal response to histamine. This maximal value over basal in control cells was a [14C]aminopyrine ratio of 21.3 ± 3.3, whereas in the cells treated with pertussis toxin the maximal response to histamine was 19.2 ± 4.6. IBMX, isobutylmethylxanthine.

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John G. Forte, Andrew Soll. Cell Biology of Hydrochloric Acid Secretion. Compr Physiol 2011, Supplement 18: Handbook of Physiology, The Gastrointestinal System, Salivary, Gastric, Pancreatic, and Hepatobiliary Secretion: 207-228. First published in print 1989. doi: 10.1002/cphy.cp060311