EDITORIAL FOCUS
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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ARTICLE |
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.
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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).
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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
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