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Parietal cell membrane trafficking Focus on "Expression of rab11a N124I in gastric parietal cells inhibits stimulatory recruitment of the H+-K+-ATPase"

Barry H. Hirst

Department of Physiological Sciences, University of Newcastle, Medical School, Newcastle upon Tyne NE2 4HH, United Kingdom


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GASTRIC JUICE is highly acidic, and pH values of <1 are possible. This intragastric environment is achieved by the secretion of a primary fluid of ~140 mM HCl by the mammalian gastric parietal or oxyntic cell. HCl secretion is elaborated across the apical membrane of the stimulated parietal cell by direct coupling to metabolic energy through the H+-K+-ATPase. The apical membrane of the stimulated parietal cell has a high permeability for K+. This allows K+ recycling across the apical membrane, the rate-limiting step, thus supplying extracytosolic K+ for use by the H+-K+-ATPase. In unstimulated or resting parietal cells, the H+-K+-ATPase is retained in cytosolic tubulovesiclar membranes with a low intrinsic permeability to K+, thus limiting unwanted acid production in the resting state (12). The intimate relationship between gastric acid secretory activity and morphological changes within the parietal cell was recognized by Golgi. In more recent years, cell physiologists have been teasing out the molecular mechanisms and their regulation.

On stimulation, the apical membrane surface area of the parietal cell increases by 5- to 10-fold. The increase in apical membrane is quantitatively equivalent to the decrease in cytosolic tubulovesicular membrane (7). The increase in apical membrane surface area has been speculated to arise by osmotic swelling of a collapsed (1) or coiled (13) tubulovesicular structure following accumulation of luminal HCl in the stimulated parietal cell. A contrasting, alternate hypothesis proposed by Forte et al. (6, 8), of membrane recruitment on stimulation followed by recycling on withdrawal of the acid secretory stimulus, currently finds almost universal favor (7, 12). Implicit in the membrane recruitment and recycling hypothesis is the assumption that the parietal cell has the appropriate machinery for docking and fusion of the tubulovesicles with the apical membrane and for their subsequent recovery. Several components associated with membrane fusion and recycling in other cell types have been identified in parietal cells and have been implicated in the recruitment of tubulovesicles during stimulation. These include docking/fusion proteins such as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), associated with both the vesicle/tubulovesicle (v-SNARE) and target apical membrane (t-SNARE). Parietal cell tubulovesicles are associated with vesicle-associated membrane protein 2, a v-SNARE, and secretory carrier membrane proteins (2). Similarly, members of the rab family of small GTP-binding proteins implicated in regulation of vesicle trafficking along both exocytotic and endocytotic pathways have been identified in gastric parietal cells, particularly rab11a and rab25 (2, 3, 10, 11).

The current article in focus by Duman et al. (Ref. 4, see page C361 in this issue) makes the key step of demonstrating directly the functional importance of rab11a in both the morphological and secretory changes on stimulation of rabbit parietal cells in primary culture. In a series of earlier studies, Goldenring and colleagues (2, 10, 11) demonstrated that rab11 is the major small GTP-binding protein in parietal cells, is associated together with the H+-K+-ATPase in parietal cell isolated tubulovesicular membranes, and is immunolocalized to tubulovescicles. In the article by Duman et al. (4), a stoichiometry of one rab11 per H+-K+-ATPase has been estimated. Goldenring's group recently demonstrated redistribution of rab11a with the H+-K+-ATPase on stimulation of parietal cells, moving from tubulovesicles to the apical secretory canaliculus (3). All these data implicate rab11a in the apical recruitment of H+-K+-ATPase membranes in the parietal cell. Duman et al. (4) used the dominant negative mutant rab11a N124I to disrupt apical redistribution of tubulovesicles on stimulation. The rab11a N124I dominant negative mutant is localized, identically to native rab11a, to cytosolic tubulovesicles in resting parietal cells. In rab11a N124I transfected cells, stimulation of parietal cell activity no longer results in the normal cellular morphological changes, including recruitment of tubulovesicles with H+-K+-ATPase to the apical membrane. This inhibition of normal morphological changes in the parietal cells is accompanied by inhibition of aminopyrine accumulation, an index of acid secretion. Thus a direct link between disruption of rab11a and inhibition of parietal cell acid secretory function has been demonstrated.

The cycling of rab proteins on and off vesicle membranes has been proposed as a critical step in vesicle trafficking. Such studies have included a variety of neuronal, exocrine, and endocrine cell types, concentrating on rab3 (5). Rab3 cycles off synaptic vesicles after exocytosis, involving ATP hydrolysis. Thus GTP-rab3 is associated with synaptic vesicles, whereas GDP-rab3 is found in the cytosol (5). Evidence from rab3A knockout mice indicates that rab3A is a constitutive negative regulator of vesicle fusion (9). In contrast, evidence to date points to the continued association of rab11a with the H+-K+-ATPase membranes after their fusion with the apical membrane (3). Thus the role of rab11a in H+-K+-ATPase membrane recruitment and recycling equates better with transferrin receptor recycling in epithelial cells than with vesicular exocytosis. In this respect, a recent report has identified at least one possible target for rab11 involvement in transferrin recycling, rab11BP (15), and it will be interesting to address whether this is expressed in parietal cells.

Now another step in the parietal cell transition from rest to secretion has been put into physiological context. Other key steps will surely follow. Key future questions in parietal cell biology must include addressing the molecular events involved in membrane retrieval following withdrawal of the secretory stimulus. In classical exocytotic cells, membrane retrieval is rapid following exocytosis. What stabilizes the apical membrane of the parietal cell? Is the activated parietal cell subverting mechanisms similar to those involved in plasma membrane repair after injury (14)? Is the recovery endocytotic step inhibited or lacking activation in the stimulated cell? The extent of membrane involved in parietal cell transition from rest to stimulation is truly large. In this respect, the parietal cell is an exciting tool for the study of the underlying molecular mechanisms in membrane trafficking and as such deserves much wider interest.


    FOOTNOTES

Address for reprint requests and other correspondence: B. H. Hirst, Department of Physiological Sciences, University of Newcastle, Medical School, Newcastle upon Tyne NE2 4HH, UK (E-mail barry.hirst{at}ncl.ac.uk).


    REFERENCES
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REFERENCES

1.   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[Abstract/Free Full Text].

2.   Calhoun, B. C., and J. R. Goldenring. Two Rab proteins, vesicle-associated membrane protein 2 (VAMP-2) and secretory carrier membrane proteins (SCAMPs), are present on immunoisolated parietal cell tubulovesicles. Biochem. J. 325: 559-564, 1997[Medline].

3.   Calhoun, B. C., L. A. Lapierre, C. S. Chew, and J. R. Goldenring. Rab11a redistributes to apical secretory canaliculus during stimulation of gastric parietal cells. Am. J. Physiol. 275 (Cell Physiol. 44): C163-C170, 1998[Abstract/Free Full Text].

4.   Duman, J. G., K. Tyagarajan, M. S. Kolsi, H.-P. H. Moore, and J. G. Forte. Expression of rab11a N124I in gastric parietal cells inhibits stimulatory recruitment of the H+-K+-ATPase. Am. J. Physiol. 277 (Cell Physiol. 46): C361-C372, 1999[Abstract/Free Full Text].

5.   Fernández-Chacón, R., and T. C. Südhof. Genetics of synaptic vesicle function: toward the complete functional anatomy of an organelle. Annu. Rev. Physiol. 61: 753-776, 1999[Medline].

6.   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[Abstract/Free Full Text].

7.   Forte, J. G., and X. Yao. The membrane-recruitment-and-recycling hypothesis of gastric HCl secretion. Trends Cell Biol. 6: 45-48, 1996.

8.   Forte, T. M., T. E. Machen, and J. G. Forte. Ultrastuctural changes in oxyntic cells associated with secretory function: a membrane recycling hypothesis. Gastroenterology 73: 941-955, 1977[Medline].

9.   Geppert, M., Y. Goda, C. F. Stevens, and T. C. Südhof. Rab3A regulates a late step in synaptic vesicle fusion. Nature 387: 810-814, 1997[Medline].

10.   Goldenring, J. R., J. Smith, H. D. Vaughan, P. Cameron, W. Hawkins, and J. Navarre. Rab11 is an apically located small GTP-binding protein in epithelial tissues. Am. J. Physiol. 270 (Gastrointest. Liver Physiol. 33): G515-G525, 1996[Abstract/Free Full Text].

11.   Goldenring, J. R., C. J. Soroka, K. R. Shen, L. H. Tang, W. Rodriguez, H. D. Vaughan, S. A. Stoch, and I. M. Modlin. Enrichment of rab11, a small GTP-binding protein, in gastric parietal cells. Am. J. Physiol. 267 (Gastrointest. Liver Physiol. 30): G187-G194, 1994[Abstract/Free Full Text].

12.   Hersey, S. J., and G. Sachs. Gastric acid secretion. Physiol. Rev. 75: 155-189, 1995[Free Full Text].

13.   Pettitt, J. M., I. R. van Driel, B.-H. Toh, and P. A. Gleeson. From coiled tubules to a secretory canaliculus: a new model for membrane transformation and acid secretion by gastric parietal cells. Trends Cell Biol. 6: 49-53, 1996.

14.   Steinhardt, R. A., G. Bi, and J. M. Alderton. Cell membrane resealing by a vesicular mechanism similar to neurotransmitter release. Science 263: 390-393, 1994[Medline].

15.   Zeng, J., M. Ren, D. Gravotta, C. de Lemos-Chiarandini, M. Lui, H. Erdjument-Bromage, P. Tempst, G. Xu, T. H. Shen, T. Morimoto, M. Adesnik, and D. D. Sabatini. Identification of a putative effector protein for rab11 that participates in transferrin recycling. Proc. Natl. Acad. Sci. USA 96: 2840-2845, 1999[Abstract/Free Full Text].


Am J Physiol Cell Physiol 277(3):C359-C360
0002-9513/99 $5.00 Copyright © 1999 the American Physiological Society




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