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) 144. 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 46a)
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 46a)
Figure 4. Figure 4.

Model for receptor regulation of canine parietal cell function. This revised model 116 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 119,121. 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 75
Figure 7. Figure 7.

Comparison of ATP‐driven H+ uptake in gastric microsomal vesicles and stimulation‐associated vesicles. As in Figure 6, 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. 98
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) 144. 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 46a)


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 46a)


Figure 4.

Model for receptor regulation of canine parietal cell function. This revised model 116 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 119,121. 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 75


Figure 7.

Comparison of ATP‐driven H+ uptake in gastric microsomal vesicles and stimulation‐associated vesicles. As in Figure 6, 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. 98


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.

References
 1. Albinus, M., and K. F. Sewing. Histamine uptake and metabolism in intact isolated parietal cells. Agents Actions 11: 223–227, 1981.
 2. Asano, S., M. Inoie, and N. Takeguchi. The CI‐ channel in hog gastric vesicles is part of the function of H,K‐ATPase. J. Biol. Chem. 262: 13263–13268, 1987.
 3. Batzri, S., and J. Dyer. aminopyrine uptake by guinea pig gastric mucosal cells: mediation by cyclic AMP and interaction among secretagogues. Biochim. Biophys. Acta 675: 416–426, 1981.
 4. Batzri, S., J. W. Harmon, and W. F. Thompson. Interaction of histamine with gastric mucosal cells: effect of histamine agonists on binding and biological response. Mol. Pharmacol. 22: 33–40, 1982.
 5. Beaven, M. A., A. H. Soll, and K. J. Lewin. Histamine synthesis by intact mast cells from canine fundic mucosa and liver. Gastroenterology 82: 254–262, 1982.
 6. Berglindh, T. Effects of common inhibitors of gastric acid secretion on secretagogue‐induced respiration and aminopyrine accumulation in isolated gastric glands. Biochim. Biophys. Acta 464: 217–233, 1977.
 7. Berglindh, T. Potentiation by carbachol and aminophylline of histamine‐ and dbcAMP‐induced parietal cells activity in isolated gastric glands. Acta Physiol. Scand. 99: 75–84, 1977.
 8. Berglindh, T. The mammalian gastric parietal cell in vitro. Annu. Rev. Physiol. 46: 377–392, 1984.
 9. Berglindh, T., D. R. Dibona, S. Ito, and G. Sachs. Probes of parietal cell function. Am. J. Physiol. 238 (Gastrointest. Liver Physiol.1): G165–G176, 1980.
 10. Berglindh, T., H. F. Helander, and K. J. Öbrink. Effects of secretagogues on oxygen consumption, aminopyrine accumulation and morphology in isolated gastric glands. Acta Physiol. Scand. 97: 401–414, 1976.
 11. Berglindh, T., and K. J. Öbrink. Histamine as a physiological stimulant of gastric parietal cells. In: Histamine Receptors, edited by T. Yellin. New York: Spectrum, 1979, p. 35–56.
 12. Berglindh, T., G. Sachs, and N. Takeguchi. Ca2+‐dependent secretagogue stimulation in isolated rabbit gastric glands. Am. J. Physiol. 239 (Gastrointest. Liver Physiol.2): G90–G94, 1980.
 13. Bergqvist, E., M. Waller, L. Hammer, and K. J. Öbrink. Histamine as the secretory mediator in isolated gastric glands. In: Hydrogen Ion Transport in Epithelia, edited by I. Schulz, G. Sachs, J. G. Forte, and K. J. Ullrich. Amsterdam: Elsevier/North‐Holland, 1980, p. 429–437.
 14. Bertaccini, G., and G. Coruzzi. Evidence for and against heterogeneity in the histamine H2‐receptor population. Pharmacology Basel 23: 1–13, 1981.
 15. Black, J. A., T. M. Forte, and J. G. Forte. Structure of oxyntic cell membranes during conditions of rest and secretion of HCl as revealed by freeze‐fracture. Anat. Rec. 196: 163–172, 1980.
 16. Black, J. A., T. M. Forte, and J. G. Forte. Inhibition of HC1 secretion and the effects of ultrastructure and electrical resistance in isolated piglet gastric mucosa. Gastroenterology 81: 509–519, 1981.
 17. Black, J. A., T. M. Forte, and J. G. Forte. The effects of microfilament disrupting agents on HC1 secretion and ultra‐structure of piglet oxyntic cells. Gastroenterology 83: 595–604, 1982.
 18. Blakemore, R. C., T. H. Brown, G. J. Duran, C. R. Ganellin, M. E. Parsons, A. C. Rasmussen, and D. A. Rawlings. SKF93479, a potent and long acting histamine H2‐receptor antagonist (Abstract). Br. J. Pharmacol. 74: 200P, 1981.
 19. Carlisle, K. S., C. S. Chew, and S. J. Hersey. Ultrastructural changes and cyclic AMP in frog gastric cells. J. Cell Biol. 76: 31–42, 1978.
 20. Carrasquer, G., T.‐C. Chu, W. S. Rehm, and M. Schwartz. Evidence for electrogenic Na‐Cl symport in the in vitro frog stomach. Am. J. Physiol. 242 (Gastrointest. Liver Physiol.5): G620–G627, 1982.
 21. Chen, M. C., D. Amirian, M. Toomey, M. Sanders, and A. H. Soll. Prostanoid inhibition of canine parietal cells: mediation by the inhibiting GTP‐binding protein of adenylate cyclase. Gastroenterology. 94: 1121–1129, 1988.
 22. Chew, C. S. Forskolin stimulation of acid and pepsinogen secretion in isolated gastric glands. Am. J. Physiol. 245 (Cell Physiol. 14): C371–C380, 1983.
 23. Chew, C. S. Parietal cell protein kinases. J. Biol. Chem. 260: 7540–7550, 1985.
 24. Chew, C. S. Cholecystokinin, carbachol, gastrin, histamine, and forskolin increase [Ca2+]i in gastric glands. Am. J. Physiol. 250 (Gastrointest. Liver Physiol.13): G814–G823, 1986.
 25. Chew, C. S., and M. R. Brown. Histamine increases phosphorylation of 27‐ and 40‐kDa parietal cell proteins. Am. J. Physiol. 253 (Gastrointest. Liver Physiol.16): G823–G829, 1987.
 26. Chew, C. S., and S. J. Hersey. Gastrin stimulation of isolated gastric glands. Am. J. Physiol. 242 (Gastrointest. Liver Physiol.5): G504–G512, 1982.
 27. Chew, C. S., S. J. Hersey, G. Sachs, and T. Berglindh. Histamine responsiveness of isolated gastric glands. Am. J. Physiol 238 (Gastrointest. Liver Physiol.1): G312–G320, 1980.
 28. Coulton, G. R., and J. A. Firth. Cytochemical evidence for functional zonation of parietal cells within the gastric glands of the mouse. Histochem. J. 15: 1141–1150, 1983.
 29. Culp, D. J., and J. G. Forte. An enriched preparation of basolateral plasma membranes from gastric glandular cells. J. Membr. Biol. 59: 135–142, 1981.
 30. Culp, D. J., J. M. Wolosin, A. H. Soll, and J. G. Forte. Muscarinic receptors and guanylate cyclase in mammalian gastric glandular cells. Am. J. Physiol. 245 (Gastrointest. Liver Physiol.8): G760–G768, 1983.
 31. Cuppoletti, J., and G. Sachs. Regulation of gastric acid secretion via modulation of a chloride conductance. J. Biol. Chem. 259: 14952–14959, 1984.
 32. Cuppoletti, J., G. Sachs, and D. H. Malinowska. Cytoskeletal proteins in gastric H+ secretion: cAMP dependent phosphorylation, immunolocalization, and protein blotting (Abstract). Federation Proc. 45: 1676, 1986.
 33. Davidson, W. D., K. L. Klein, K. Kurokawa, and A. H. Soll. Instantaneous and continuous measurement of 14C‐labeled substrate oxidation to 14CO2 by minute tissue specimens: an ionization chamber method. Metabolism 30: 596–600, 1981.
 34. Demarest, J. R., and T. E. Machen. Microelectrode measurements from oxyntic cells in intact Necturus.gastric mucosa. Am. J. Physiol. 249 (Cell Physiol. 18): C535–C540, 1985.
 35. Dial, E., W. J. Thompson, and G. C. Rosenfeld. Isolated parietal cells: histamine response and pharmacology. J. Pharmacol. Exp. Ther. 219: 585–590, 1981.
 36. Ecknauer, R., E. Dial, W. J. Thompson, L. R. Johnson, and G. C., Rosenfeld. Isolated rat gastric parietal cells: cholinergic response and pharmacology. Life Sci. 28: 609–621, 1981.
 37. Ecknauer, R., W. J. Thompson, L. R. Johnson, and G. C. Rosenfeld. Isolated parietal cells: [3H]QNB binding to putative cholinergic receptors. Am. J. Physiol. 239 (Gastrointest. Liver Physiol.2): G204–G209, 1980.
 38. Eltze, M., S. Gönne, R. Riedel, B. Schlotke, C. Schudt, and W. A. Simon. Pharmacological evidence for selective inhibition of gastric acid secretion by telenzepine, a new antimuscarinic drug. Eur. J. Pharmacol. 112: 211–224, 1985.
 39. Farley, R. A., and L. D. Faller. The amino acid sequence of an active site peptide from the H,K‐ATPase of gastric mucosa. J. Biol. Chem. 260: 3899–3901, 1985.
 40. Fellenius, E., B. Elander, B. Wallmark, U. Haglund, H. F. Helander, and h. Olbe. A micro‐method for the study of acid secretory function in isolated human oxyntic glands from gastroscopic biopsies. Clin. Sci 64: 423–431, 1983.
 41. Forte, J. G., J. A. Black, T. M. Forte, T. E. Machen, and J. M. Wolosin. Ultrastructural changes related to functional activity in gastric oxyntic cells. Am. J. Physiol. 241 (Gastrointest. Liver Physiol.4): G349–G358, 1981.
 42. Forte, J. G., G. M. Forte, and P. Saltman. K+‐stimulated phosphatase in microsomes isolated from gastric mucosa. J. Cell. Physiol. 69: 175–189, 1967.
 43. Forte, J. G., and T. M Forte. Histochemical staining and characterization of glycoproteins in acid‐secreting cells of frog stomach. J. Cell Biol. 47: 437–452, 1970.
 44. Forte, J. G., A. L. Ganser, R. C. Beesley, and T. M. Forte. Unique enzymes of purified microsomes from pig fundic mucosa. Gastroenterology 69: 175–189, 1975.
 45. Forte, J. G., A. L. Ganser, and T. K. Ray. The K+‐stimulated ATPase from oxyntic glands of gastric mucosa. In: Gastric Hydrogen Ion Secretion, edited by D. K. Kasbekar, G. Sachs, and W. Rehm. New York: Dekker, 1976, p. 302–330.
 46. Forte, J. G., and D. J. Keeling. Cellular recycling of gastric H,K‐ATPase with stimulation and inhibition of HC1 secretion. FASEB J. 2: 1275A, 1988.
 47. Forte, J. G., and T. E. Machen. Ion transport by gastric mucosa. In: Physiology of Membrane Disorders, edited by T. E. Andreoli, J. F. Hoffman, D. D. Fanestil, and S. G. Schultz. New York: Plenum, 1986, p. 535–558.
 48. Forte, T. M., and J. G. Forte. Definition of extracellular space in secreting and non‐secreting cells. J. Cell Biol. 47: 782–786, 1970.
 49. Forte, T. M., T. E. Machen, and J. G. Forte. Ultrastructural changes in oxyntic cells associated with secretory function: a membrane recycling hypothesis. Gastroenterology 73: 941–955, 1977.
 50. Ganser, A. L., and J. G. Forte. Ionophoretic stimulation of K+‐ATPase of oxyntic cell microsomes. Biochem. Biophys. Res. Commun. 54: 690–696, 1973.
 51. Ganser, A. L., and J. G. Forte. K+‐stimulated ATPase in purified microsomes of bullfrog oxyntic cells. Biochim. Biophys. Acta 307: 169–180, 1973.
 52. Gespach, C., D. Bouhours, J. F. Bouhours, and G. Rosselin. Histamine interaction on surface recognition sites of H2‐type in parietal and nonparietal cells isolated from the guinea pig stomach. FEBS Lett. 149: 85–90, 1982.
 53. Gibert, A. J., and S. J. Hersey. Morphometric analysis of parietal cell membrane transformations in isolated gastric glands. J. Membr. Biol. 67: 113–124, 1982.
 54. Golgi, C. Sur la fine organisation des glandes peptiques des mammiferes. Arch. Ital. Biol. 19: 448–453, 1893.
 55. Grinstein, S., C. A. Cohen, and A. Rothstein. Cytoplasmic pH regulation in thymic lymphocytes by an amiloride‐sensitive Na+/H+ antiport. J. Gen. Physiol. 83: 341–369, 1984.
 56. Gunther, R. D., S. Bassilian, and E. Rabon. Cation transport in vesicles from secreting rabbit stomach. J. Biol. Chem. 262: 13966–13972, 1987.
 57. Hahne, W. F., R. T. Jensen, G. F. Lamp, and J. D. Gardner. Proglumide and benzotript: members of a different class of cholecystokinin receptor antagonists. Proc. Natl. Acad. Sci. USA 10: 6304–6308, 1981.
 58. Hakanson, R., G. Bottcher, E. Ekblad, P. Panula, M. Simonsson, M. Dohlsten, T. Hallberg, and F. Sundler. Histamine in endocrine cells in the stomach: a survey of several species using a panel of histamine antibodies. Histochemistry 86: 5–17, 1986.
 59. Harris, J. B., and D. Alonso. Stimulation of the gastric mucosa by adenosine‐3',5'‐monophosphate. Federation Proc. 24: 1368–1376, 1965.
 60. Harris, J. B., and I. S. Edelman. Chemical concentration gradients and electrical properties of gastric mucosa. Am. J. Physiol. 206: 769–782, 1964.
 61. Helander, H. F. The cells of the gastric mucosa. Int. Rev. Cytol. 70: 217–289, 1981.
 62. Helander, H. F., and B. I. Hirschowitz. Quantitative ultrastructural studies of microvilli and changes in the tubulovesicular compartment of mouse parietal cells in relation to gastric acid secretion. J. Cell Biol. 63: 951–961, 1972.
 63. Helander, H. F., and G. W. Sundell. Ultrastructure of inhibited parietal cells in the rat. Gastroenterology 87: 1064–1071, 1984.
 64. High, W. L., and S. J. Hersey. Mechanism of theophylline stimulation of acid secretion by frog gastric mucosa. Am. J. Physiol. 226: 1408–1412, 1974.
 65. Hirschowitz, B. I., J. Fong, and E. Molina. Effects of pirenzepine and atropine on vagal and cholinergic gastric secretion and gastric release and on heart rate in the dog. J. Pharmacol. Exp. Ther. 225: 263–268, 1983. Hirst, B. H., and J. G. Forte. Redistribution and characterization of (H+ + K+)‐ATPase membranes from resting and stimulated gastric parietal cells. Biochem. J. 231: 641–649, 1985.
 66. Hopfer, U., and C. M. Liedtke. Proton and bicarbonate transport mechanisms in the intestine. Annu. Rev. Physiol. 49: 51–67, 1987.
 67. Im, W. B., D. P. Blakeman, J. E. Bleasdale, and J. P. Davis. A protein phosphatase associated with rat heavy gastric membranes enriched with (H+‐K+)‐ATPase influences membrane K+ transport activity. J. Biol. Chem. 262: 9865–9871, 1987.
 68. Im, W. B., D. P. Blakeman, and J. P. Davis. Studies on K+ permeability of rat gastric microsomes. J. Biol. Chem. 260: 9452–9460, 1985.
 69. Ito, S. Functional gastric morphology. In: Physiology of the Gastrointestinal Tract. (2nd ed.), edited by L. R. Johnson. New York: Raven, 1987, vol. 1, p. 817–851.
 70. Ito, S., and G. C. Schofield. Studies on the depletion and accumulation of microvilli and changes in the tubulovesicular compartment of mouse parietal cells in relation to gastric acid secretion. J. Cell Biol. 63: 364–382, 1974.
 71. Jacobs, D. M., and R. P. Sturtevant. Circadian ultrastructural changes in rat gastric parietal cells under altered feeding regimens: a morphometric study. Anat. Rec. 203: 101–113, 1982.
 72. Kasbekar, D. K., and G. S. Gordon. Effects of colchicine and vinblastine on in vitro gastric secretion. Am. J. Physiol. 236 (Endocrinol. Metab. Gastrointest. Physiol.5): E550–E555, 1979.
 73. Kasbekar, D. K., and H. E. Stewart. Colchicine binding activity of the frog gastric mucosa. In: Hydrogen Ion Transport in Epithelia, edited by I. Schulz, G. Sachs, J. G. Forte, and K. J. Ullrich. New York: Elsevier, 1980, p. 105–112.
 74. Larsson, H., E. Carlsson, H. Mattsson, K. Lundell, F. Sundler, G. Sundell, B. Wallmark, T. Watanabe, and R. Hakanson. Plasma gastrin and gastric enterochromaffin‐like cell activation and proliferation. Gastroenterology 90: 391–399, 1986.
 75. Lee, H. C., H. Breitbart, M. Berman, and J. G. Forte. Potassium‐stimulated ATPase activity and H+ transport in gastric microsomal vesicles. Biochim. Biophys. Acta 553: 107–131, 1979.
 76. Lee, H. C., and J. G Forte. A study of H+ transport in gastric microsomal vesicles using fluorescent probes. Biochim. Biophys. Acta 508: 339–356, 1978.
 77. LeFevre, M. E., E. J. Gohmann, Jr., and W. S. Rehm. An hypothesis for discovery of inhibitors of gastric acid secretion. Am. J. Physiol. 207: 613–618, 1964.
 78. Levine, R. A., K. R. Kohen, E. H. Schwartzel,Jr., and C. E. Ramsay. Prostaglandin E2‐histamine interactions on cAMP, cGMP, and acid production in isolated fundic glands. Am. J. Physiol. 242 (Gastrointest. Liver Physiol.5): G21–G26, 1982.
 79. Lipkin, M. Proliferation and differentiation of gastrointestinal cells. Physiol. Rev. 53: 891–915, 1973.
 80. Machen, T. E., and W. L. McLennan. Na+‐dependent H+ and Cl‐ transport in in vitro frog gastric mucosa. Am. J. Physiol. 238 (Gastrointest. Liver Physiol.1): G403–G413, 1980.
 81. Machen, T. E., and A. M. Paradiso. Regulation of intracellular pH in the stomach. Annu. Rev. Physiol. 49: 19–33, 1987.
 82. Major, J. S., and P. Scholes. The localization of a histamine H2‐receptor adenylate cyclase system in canine parietal cells and its inhibition by prostaglandins. Agents Actions 8: 324–331, 1978.
 83. McLennan, W. L., T. E. Machen, and T. Zeuthen. Ba2+ inhibition of electrogenic Cl‐ secretion in vitro frog and piglet gastric mucosa. Am. J. Physiol. 239 (Gastrointest. Liver Physiol.2): G151–G160, 1980.
 84. Michelangeli, F. Isolated oxyntic cells: physiological characterization. In: Gastric Hydrogen Ion Secretion, edited by D. K. Kasbekar, G. Sachs, and W. S. Rehm. New York: Dekker, 1976, p. 212–236.
 85. Miller, M., and A. J. Hersey. Cyclic nucleotide‐dependent protein kinase from isolated gastric glands. In: Hydrogen Ion Transport in Epithelia, edited by J. G. Forte, D. G. Warnock, and F. C. Rector. New York: Wiley, 1984, p. 353–362.
 86. Muallem, S., C. Burnham, D. Blissard, T. Berglindh, and G. Sachs. Electrolyte transport accross basolateral membrane of the parietal cells. J. Biol. Chem. 260: 6644–6653, 1985.
 87. Muallem, S., and G. Sachs. Changes in cytosolic free Ca2+ in isolated parietal cells. Differential effects of secretagogues. Biochim. Biophys. Acta 805: 181–185, 1984.
 88. Muallem, S., and G. Sachs. Ca2+ metabolism during cholinergic stimulation of acid secretion. Am. J. Physiol. 248 (Gastrointest. Liver Physiol.11): G216–G228, 1985.
 89. Negulescu, P. A., and T. E. Machen. Intracellular Ca regulation during secretagogus stimulation of the parietal cell. Am. J. Physiol. 254 (Cell Physiol. 23): C130–C140, 1988.
 90. Negulescu, P. A., and T. E. Machen. Release and reloading of intracellular Ca stores after cholinergic stimulation of the parietal cell. Am. J. Physiol. 254 (Cell Physiol. 23): C498–C504, 1988.
 91. Nylander, O., T. Berglindh, and K. J. Öbrink. Prostaglandin interaction with histamine release and parietal cell activity in isolated gastric glands. Am. J. Physiol. 250 (Gastrointest. Liver Physiol. 13): G607–G616, 1986.
 92. Paradiso, A. M., and T. E. Machen. Histamine activates H/K‐ATPase and Na/H and Cl/HCO3 exchange in oxyntic cells (OC). FASEB J. 2: 1727A, 1988.
 93. Paradiso, A. M., P. A. Negulescu, and T. E. Machen. Na+‐H+ and Cl‐OH‐(HCO‐3) exchange in gastric glands. Am. J. Physiol. 250 (Gastrointest. Liver Physiol.13): G524–G534, 1986.
 94. Paradiso, A. M., R. Y. Tsien, and T. E. Machen. Na+‐H+ exchange in gastric glands as measured with a cytoplasmictrapped, fluorescent pH indicator. Proc. Natl. Acad. Sci. USA 81: 7436–7440, 1984.
 95. Rabon, E., H. Chang, and G. Sachs. Quantitation of hydrogen ion and potential gradients in gastric plasma membrane vesicles. Biochemistry 17: 3345–3353, 1978.
 96. Rabon, E., G. Saccomani, D. K. Kasbekar, and G. Sachs. Transport characteristics of frog gastric membranes. Biochem. Biophys. Acta 551: 432–447, 1987.
 97. Ragins, H., F. Wincze, S. M. Liu, and M. Dittenbrenner. The origin and survival of gastric parietal cells in the mouse. Anat. Rec. 162: 99–110, 1968.
 98. Reenstra, W. W., J. D. Bettencourt, and J. G. Forte. Active K+ absorption by the gastric mucosa: inhibition by omeprazole. Am. J. Physiol. 250 (Gastrointest. Liver Physiol.13): G455–G460, 1986.
 99. Reenstra, W. W., J. D. Bettencourt, and J. G. Forte. Mechanism of active Cl‐ secretion by frog gastric mucosa. Am. J. Physiol. 252 (Gastrointest. Liver Physiol.15): G543–G547, 1987.
 100. Reenstra, W. W., and J. G. Forte. Action of thiocyanate on pH gradient formation by gastric microsomal vesicles. Am. J. Physiol. 244 (Gastrointest. Liver Physiol.7): G308–G313, 1983.
 101. Reenstra, W. W., and J. G. Forte. Mechanism of inhibition of gastric acid secretion by SCN‐: interrelation of SCN‐ flux and inhibition. Am. J. Physiol. 260 (Gastrointest. Liver Physiol.13): G76–G84, 1986.
 102. Rehm, W. S. Ion permeability and electrical resistance of the frog's gastric mucosa. Federation Proc. 26: 1303–1313, 1967.
 103. Rehm, W. S., T.‐C. Chu, M. Schwartz, and G. Carrasquer. Mechanisms responsible for SCN increase in resistance of in vitro frog gastric mucosa. Am. J. Physiol. 245 (Gastrointest. Liver Physiol.8): G143–G156, 1983.
 104. Reuss, L., and J. S. Stoddard. Role of H+ and HCO‐3 in salt transport in gallbladder epithelium. Annu. Rev. Physiol. 49: 35–49, 1987.
 105. Rising, T. J., D. B. Norris, S. E. Warrander, and T. P. Wood. High affinity 3H‐cimetidine binding in guinea‐pig tissues. Life Sci. 27: 199–206, 1980.
 106. Romrell, L. J., M. R. Coppe, D. R. Munro, and S. Ito. Isolation and separation of highly enriched fractions of viable mouse gastric parietal cells by velocity sedimentation. J. Cell Biol. 65: 428–438, 1975.
 107. Rosenfeld, G. C. Pirenzepine (LS 519): a weak inhibitor on acid secretion by isolated rat parietal cells. Eur. J. Pharmacol. 86: 99–101, 1983.
 108. Saccomani, G., H. F. Helander, S. Crago, H. H. Chang, and G. Sachs. Characterization of gastric mucosal membranes. X. Immunological studies of gastric (H+ + K+)‐AT‐Pase. J. Cell Biol. 83: 271–283, 1979.
 109. Sachs, G., H. H. Chang, E. Rabon, R. Schackmann, M. Lewin, and G. Saccomani. A non‐electrogenic H+ pump in plasma membranes of hog stomach. J. Biol. Chem. 251: 7690–7698, 1976.
 110. Sachs, G., D. K. Kasbekar, and T. Berglindh. The mechanism of action of pirenzepine on gastric secretion. In: Die Behandlung des ulcus pepticum mit perenzepin, edited by A. L. Blum, Z. Biberach, and R. H. Demeter. Berlin: Springer‐Verlag, 1978, p. 18–34.
 111. Schackmann, R. A., A. Schwartz, G. Saccomani, and G. Sachs. Cation transport by gastric H+ + K+ ATPase. J. Membr. Biol. 32: 361–381, 1977.
 112. Schepp, W., H.‐K. Heim, and H.‐J. Ruoff. Comparison of the effect of PGE2 and somatostatin on histamine stimulated 14C‐aminopyrine uptake and cyclic AMP formation in isolated rat gastric mucosal cells. Agents Actions 13: 200–206, 1983.
 113. Sedar, A. W. Uptake of peroxidase into the smooth‐surfaced tubular system of the gastric acid‐secreting cell. J. Cell Biol. 43: 179–184, 1969.
 114. Shull, G. E., and J. B. Lingrel. Molecular cloning of the rat stomach (H+ + K+)‐ATPase. J. Biol. Chem. 261: 16788–16791, 1986.
 115. Skoglund, M. L., A. S. Nies, and J. G. Gerber. Inhibition of acid secretion in isolated canine parietal cells by prostaglandins. J. Pharmacol. Exp. Ther. 220: 371–374, 1982.
 116. Smolka, A., H. F. Helander, and G. Sachs. Monoclonal antibodies against gastric H+ + K+ ATPase. Am. J. Physiol. 245 (Gastrointest. Liver Physiol.8): G589–G596, 1983.
 117. Soll, A. H. The actions of secretagogues on oxygen uptake by isolated mammalian parietal cells. J. Clin. Invest. 61: 370–380, 1978.
 118. Soll, A. H. The interaction of histamine with gastrin and carbamylcholine on oxygen uptake by isolated mammalian parietal cells. J. Clin. Invest. 61: 381–389, 1978.
 119. Soll, A. H. Specific inhibition by prostaglandins E2 and I2 of histamine‐stimulated [14C]aminopyrine accumulation and cyclic adenosine monophosphate generated by isolated canine parietal cells. J. Clin. Invest. 65: 1222–1229, 1978.
 120. Soll, A. H. Secretagojiue stimulation of [14C]aminopyrine accumulation by isolated canine parietal cells. Am. J. Physiol. 238 (Gastrointest. Liver Physiol.1): G366–G375, 1980.
 121. Soll, A. H. Extracellular calcium and cholinergic stimulation of isolated canine parietal cells. J. Clin. Invest. 68: 270–278, 1981.
 122. Soll, A. H., D. A. Amirian, L. P. Thomas, J. Park, J. D. Elashoff, M. A. Beavan, and T. Yamada. Gastrin receptors on nonparietal cells isolated from canine fundic mucosa. Am. J. Physiol. 247 (Gastrointest. Liver Physiol.10): G715–G723, 1984.
 123. Soll, A. H., D. A. Amirian, L. P. Thomas, T. J. Reedy, and J. D. Elashoff. Gastrin receptors on isolated canine parietal cells. J. Clin. Invest. 73: M34–1447, 1984.
 124. Soll, A. H., and T. Berglindh. Physiology of isolated gastric glands and parietal cells:: receptors and effectors regulating function. In: Physiology of the Gastrointestinal Tract. (2nd ed.), edited by L. R. Johnson. New York: Raven, 1987, vol. 1, p. 883–909.
 125. Soll, A. H., K. Lewin, and M. A. Beaven. Isolation of histamine containing cells from canine fundic mucosa. Gastroenterology 77: 1283–1290, 1979.
 126. Soll, A. H., M. Toomey, D. Culp, F. Shanahan, and M. A. Beaven. Modulation of histamine release from canine fundic mucosal mast cells. Am. J. Physiol. 254 (Gastrointest. Liver Physiol.17): G40–G48, 1988.
 127. Soll, A. H., T. Yamada, J. Park, and L. P. Thomas. Release of somatostatinlike immunoreactivity from canine fundic mucosal cells in primary culture. Am. J. Physiol. 247 (Gastrointest. Liver Physiol. 10): G558–G566, 1984.
 128. Sonnenberg, A., W. Huinziker, H. R. Koelz, J. A. Fischer, and A. L. Blum. Stimulation of endogenous cyclic AMP (cAMP) in isolated gastric cells by histamine and prostaglandin. Acta Physiol. Scand. Suppl. 307–317, 1978.
 129. Soumarmon, A., A. M. Cheret, and M. J. M. Lewin. Localization of gastrin receptors in intact isolated and separated fundic rat cells. Gastroenterology 73: 900–903, 1978.
 130. Spangler, S. G., and W. S. Rehm. Potential responses of nutrient membrane of frog's stomach to step changes in external K+ and Cl‐ concentrations. Biophys. J. 8: 1211–1227, 1968.
 131. Takeguchi, N., M. Hatrori, A. Sano, and I. Horikoshi. Intracellular potassium ion in relation to acid secretory rate by frog gastric mucosa. Am. J. Physiol. 237 (Endocrinol. Metab. Gastrointest. Physiol.6): E51–E55, 1979.
 132. Takeguchi, N., R. Joshima, Y. Inoue, T. Kashiwagura, and M. Morii. Effects of Cu2+‐o.phenanthroline on gastric (H+ + K+)‐ATPase. Evidence for opening of a closed anion conductance by S‐S cross‐linkings. J. Biol. Chem. 258: 3094–3098, 1983.
 133. Takeguchi, N., and Y. Yamazaki. Disulfide cross‐linking of H,K‐ATPase opens Cl‐ conductance, triggering proton uptake in gastric vesicles. Studies with specific inhibitors. J. Biol. Chem. 261: 2560–2566, 1986.
 134. Takuchi, R., G. R. Speir, and L. R. Johnson. Mucosal gastric receptor. I. Assay standardization and fulfillment of receptor criteria. Am. J. Physiol. 237 (Endocrinol. Metab. Gastrointest. Physiol.6): E284–E294, 1979.
 135. Urushidani, T., D. K. Hanzel, and J. G. Forte. Protein phosphorylation associated with stimulation of rabbit gastric glands. Biochim, Biophys. Acta 930: 209–219, 1987.
 136. Vial, J. D., and J. Garrido. Actin‐like filaments and membrane rearrangement of oxyntic cells. Proc. Natl. Acad. Sci. USA 73: 4032–4036, 1976.
 137. Wallmark, B., G. Sachs, S. Mardh, and E. Fellenius. Inhibition of gastric (H+ + K+)‐ATPase by the substituted benzimidazole, picoprazole. Biochim. Biophys. Acta 728: 31–38, 1983.
 138. Wollin, A., L. D. Barnes, Y. S. Hui, and T. P. Dousa. Activation of protein kinase in the guinea pig fundic gastric mucosa by histamine. Life Sci. 17: 1303–1306, 1974.
 139. Wollin, A., A. H. Soll, and I. M. Samloff. Actions of histamine, secretin, and PGE2 on cyclic AMP production by isolated canine fundic mucosal cells. Am. J. Physiol. 237 (Endocrinol. Metab. Gastrointest. Physiol.6): E437–E443, 1979.
 140. Wolosin, J. M., and J. G. Forte. Changes in the membrane environment of the (K+ + H+)‐ATPase following stimulation of the gastric oxyntic cell. J. Biol. Chem. 256: 3149–3152, 1981.
 141. Wolosin, J. M., and J. G. Forte. Functional differences between K+‐ATPase‐rich membrane isolated from resting and stimulated rabbit fundic mucosa. FEBS Lett. 125: 208–212, 1981.
 142. Wolosin, J. M., and J. G. Forte. Kinetic properties of the KCl transport at the secreting apical membrane of the oxyntic cell. J. Membr. Biol. 71: 195–207, 1983.
 143. Wolosin, J. M., and J. G. Forte. Stimulation of oxyntic cell triggers K+ and Cl‐ conductances in apical H+ + K+‐ATPase membrane. Am. J. Physiol. 246 (Cell Physiol. 15): C537–C545, 1984.
 144. Wolosin, J. M., and J. G. Forte. K+ and Cl‐ conductances in the apical membrane from secreting oxyntic cells are concurrently inhibited by divalent cations. J. Membr. Biol. 83: 261–272, 1985.
 145. Wolosin, J. M., C. Okamoto, T. M. Forte, and J. G. Forte. Actin and associated proteins in gastric epithelial cells. Biochim. Biophys. Acta 761: 171–182, 1983.
 146. Yamada, T., A. H. Soll, J. Park, and J. Elashoff. Autonomic regulation of somatostatin release: studies with primary cultures of canine fundic mucosal cells. Am. J. Physiol. 247 (Gastrointest. Liver Physiol. 10): G567–G573, 1984.
 147. Zalewsky, C. A., and F. G. Moody. Stereological analysis of the parietal cell during acid secretion and inhibition. Gastroenterology 73: 66–74, 1977.

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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