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(Received for publication, December 24, 1996, and in revised form, March 6, 1997)
From the ABSTRACT Although secretin is known to stimulate ductal
bile secretion by directly interacting with cholangiocytes, the precise
cellular mechanisms accounting for this choleretic effect are unknown. We have previously shown that secretin stimulates exocytosis in cholangiocytes and that these cells transport water mainly via the
water channel aquaporin-1 (AQP1). In this study, we tested the
hypothesis that secretin promotes osmotic water movement in cholangiocytes by inducing the exocytic insertion of AQP1 into plasma
membranes. Exposure of highly purified isolated rat cholangiocytes to
secretin caused significant, dose-dependent increases in
osmotic membrane water permeability (Pf)
(e.g. increased by 60% with 10 INTRODUCTION Bile is formed primarily by hepatocytes and secreted at the bile
canaliculus; subsequently, its volume and composition are modified in
the lumen of bile ducts as a result of the transport of water and
solutes by cholangiocytes (1, 2). While this ductal bile secretion
results from the osmotically driven movement of water, the regulatory
and mechanistic aspects are obscure. We recently reported that
cholangiocytes (unlike hepatocytes) express the water-selective channel
protein aquaporin-1 (AQP1)1 and proposed
that ductal bile secretion results from the movement of water across
this protein (3, 4). Based on studies in renal epithelial cells, it is
currently thought that AQP1 is constitutively inserted into plasma
membranes and is not hormone responsive (5, 6).
Secretin is known to stimulate ductal bile secretion via specific
receptors on cholangiocytes (7). We and others recently proposed that
secretin-induced bile secretion was associated with the
microtubule-dependent exocytic insertion of cytoplasmic
vesicles into the cholangiocyte plasma membrane (8-10). Interestingly, hormone-regulated exocytic movement of transporters has been
demonstrated in other cell types (11). For example, in renal collecting
tubule cells the water channel aquaporin-2 moves to and from the apical plasma membrane in the presence and absence of vasopressin,
respectively (12). For these reasons, we hypothesized that secretin
stimulates ductal bile secretion by inducing the translocation of
functional AQP1 water channels into the plasma membrane of
cholangiocytes.
MATERIALS AND METHODS Cholangiocytes
(>95% pure) were isolated from livers of male Fischer rats by
enzymatic digestion and mechanical disruption and then immunopurified
using Dynabeads M-450 and collected with a magnet as described
previously (13). In colchicine and low temperature studies,
cholangiocytes were prepared from rats 3 weeks after bile duct
ligation, a maneuver that induces selective proliferation of
cholangiocytes and thus generates an increased number of cells
available for experiments. These cholangiocytes retain normal
phenotypic features (14) and respond to secretin in a manner similar to
cholangiocytes from normal rats (15). In all experiments, cell
viability was greater than 90% as assessed by trypan blue exclusion.
All incubations were carried out in Krebs-Ringer-HEPES buffer, pH
7.4.
Following isolation, cells were incubated according to one of three
protocols: (a) for 15 min at 37 °C in the presence of 0-10 Following incubation as
described above, cells were washed and suspended in cold, 300 mosMKrebs-Ringer-HEPES buffer, pH 7.4, without
CaCl2. We have previously reported that osmotic water transport in cholangiocytes is not significantly affected at low temperature (3). Therefore, in this work water transport studies were
performed at 4 °C to prevent exo- and endocytic events in cholangiocytes (10) that could potentially modify a secretin-induced subcellular relocation of AQP1. The size of cholangiocytes was determined by quantitative phase contrast microscopy, a methodology previously validated (3, 4). Briefly, serial photographs of the same
group of cells placed on coverslips coated with polylysine in isotonic
(300 mosM) and hypotonic media (30 mosM) were
digitized, and cell diameters were measured with an image analysis
software program (ANALYZETM, Mayo Foundation). Cell volumes
were estimated based on the spherical shape of cholangiocytes using
4.5-µm immunomagnetic beads as internal standards. The osmotic
membrane water permeability (Pf) was calculated from
the initial rate of cell swelling as described previously (3).
In some experiments, cholangiocytes were incubated with the known water
channel blocker, HgCl2, for 5 min or with HgCl2
followed by 10 min with 2-mercaptoethanol before measuring water
permeability; our previous work had shown that HgCl2 at the
concentration used (0.3 mM) was not toxic for
cholangiocytes (3).
Plasma and
microsomal membrane fractions were prepared from the incubated cells by
differential centrifugation. Briefly, cholangiocytes were washed and
sonicated in 0.3 M sucrose containing 0.01% soybean trypsin inhibitor, 0.1 mM phenylmethanesulfonyl fluoride,
and 0.1 mM leupeptin (Sigma). The immunomagnetic beads were
separated using a magnet.
The plasma membrane fraction was obtained by centrifugation at
200,000 × g for 60 min on a discontinuous 1.3 M sucrose gradient as described previously (16). After
removing the plasma membrane band, the sucrose gradient was sonicated,
diluted to 0.3 M, and centrifuged at 17,000 × g for 30 min. The pellet obtained was designated
"remaining intracellular membrane fraction," and the resulting
supernatant was centrifuged at 200,000 × g for 60 min to yield the microsomal membrane fraction.
Protein concentration was determined by the fluorescamine method using
bovine serum albumin as standard (17). Alkaline phosphatase activity (a
plasma membrane marker) was assessed using a commercially available
enzyme kit (Sigma). Microsomal esterase activity (a marker for the
endoplasmic reticulum) was measured by the method of Beaufay and
Berthet (18).
Solubilized cholangiocyte membrane
fractions were subjected to SDS-polyacrylamide gel electrophoresis and
transferred to nitrocellulose sheets. After blocking, blots were
incubated overnight at 4 °C with AQP1 antiserum (19) diluted 1:500.
The blots were then washed and incubated with horseradish
peroxidase-conjugated goat antirabbit immunoglobulin (Tago, Inc.,
Burlingame, CA), and bands were detected by the enhanced
chemiluminescence detection system (ECL, Amersham). Autoradiographs
were obtained by exposing nitrocellulose sheets to Kodak XAR film, and
the bands were quantitated by laser densitometry.
RESULTS The time course of relative cholangiocyte volume
in response to an outwardly directed NaCl gradient is shown in Fig.
1A. The osmotic gradient caused water influx
and cell swelling. The rate of the swelling response was significantly
increased by 10
Together these data suggest that secretin promotes osmotic water
transport in cholangiocytes via a mechanism mediated by
mercury-sensitive water channels.
To investigate whether secretin increased
cholangiocyte Pf by inducing the translocation of
the mercury-sensitive water channel AQP1 from subcellular organelles to
cell surface, we performed quantitative immunoblotting of cholangiocyte
intracellular and plasma membranes. AQP1 protein was mostly recovered
in cholangiocyte plasma and microsomal membranes, with only negligible
amounts of AQP1 present in the remaining intracellular membrane
fraction (see "Preparation of Subcellular Membrane Fractions" under
"Materials and Methods"). Exposure of cells to secretin resulted in
an increase of AQP1 in cholangiocyte plasma membranes by (192%,
p < 0.01) and a simultaneous decrease of AQP1 in
microsomes (56%, p < 0.01) (Fig. 2).
Secretin did not alter either the yields of total membrane protein, the
specific activity of microsomal esterase, or plasma membrane alkaline
phosphatase in the cholangiocyte plasma and microsomal membrane
fractions (data not shown).
These data are consistent with a secretin-induced relocation
(presumably via vesicles) of AQP1 from intracellular to plasma membranes.
To
provide support for our interpretation that secretin-induced AQP1
redistribution in cholangiocytes involves a vesicular transport
mechanism, we evaluated the effect of two perturbations reported by us
to disturb secretin-induced exocytosis in cholangiocytes, i.e. treatment with the microtubule blocker colchicine and
exposure at low temperature (10).
Pretreatment of cholangiocytes with colchicine (but not with its
inactive analog
Together, these data suggest that secretin promotes osmotic water
transport in cholangiocytes by inducing the temperature- and microtubule-dependent vesicular translocation of
AQP1 from an intracellular compartment to plasma membrane.
DISCUSSION Current concepts concerning hormonal regulation of cell membrane
water permeability come primarily from studies of the kidney. In the
renal collecting duct, vasopressin binds to its receptor on the
basolateral membrane of tubular principal cells; the intracellular levels of cyclic AMP rise; intracellular vesicles containing AQP2 water
channels fuse with the apical membrane; and water transport increases
(21, 22). In contrast, the homologous water channel AQP1 is thought to
be constitutively expressed in plasma membranes of renal cells
(i.e. in proximal tubules and the descending limbs of Henle)
and other transporting epithelia (e.g. lung, trachea, eye,
pancreas, etc.) (5, 6, 12). Thus, our study in cholangiocytes provides
the first evidence for hormone-regulated membrane insertion of AQP1
water channels.
Secretin is known to stimulate ductal bile secretion by binding to its
receptor on the basolateral domain of cholangiocytes (7), a
ligand-receptor interaction that also activates cyclic AMP. Cyclic AMP
then activates cystic fibrosis transmembrane regulator Cl Our data demonstrate that secretin significantly increased
cholangiocyte water permeability, an effect that was reversibly inhibited by the known water channel blocker HgCl2. These
results indicate that the mercury-sensitive water channel AQP1 mediates the secretin-induced increase in cholangiocyte Pf.
Although the mercury-sensitive water channel AQP2 is not expressed in
cholangiocytes,2 we cannot exclude that other,
as yet unidentified, mercury-sensitive water channels contribute to the
secretin effect.
The dose-response relationship of the secretin-stimulated increase in
cholangiocyte Pf showed a progressive rise up to
10 As the functional studies suggested, secretin markedly increased the
amount of AQP1 in cholangiocyte plasma membranes while simultaneously
decreasing the amount of AQP1 in microsomes (Fig. 2). Based on the
quantitative immunoblots for AQP1 and the total membrane proteins in
each cholangiocyte membrane fraction, we estimated that under basal
(non-stimulated) conditions approximately 70% of the total amount of
cholangiocyte AQP1 would reside in intracellular membranes, whereas the
rest would be present in plasma membranes (i.e. ~30%).
Interestingly, in cells in which AQP1 is constitutively expressed, most
of the water channel (~95%) is associated with plasma membranes (5,
6). After secretin treatment, AQP1 became predominant in plasma
membranes (i.e. about 65% of total), and this increase was
proportional to the decrease of AQP1 observed in microsomes; the total
amount of AQP1 in both membrane fractions was not affected by secretin.
The estimated subcellular distributions of AQP1 in basal and
secretin-stimulated cholangiocytes are in very good agreement with
those reported for other hormone-regulated transporters, such as
aquaporin 2 and GLUT 4 (24-26). It is important to mention that minor
levels of cross-contamination (about 10%) between plasma and
microsomal membrane fractions were observed, but this did not
significantly affect the calculations. Thus, the stoichiometric nature
of this relationship further supports a redistribution of preexisting AQP1 water channels from an unidentified intracellular pool (associated with microsomal membranes) to cholangiocyte plasma membrane in response
to secretin.
The fact that the secretin-induced relocation of AQP1 as well as the
increased cholangiocyte Pf was disturbed by two
perturbations (Figs. 3 and 4) that block secretin-induced exocytosis in
cholangiocytes (10) (i.e. treatment with colchicine and
exposure to low temperature) is consistent with the view that a
microtubule-dependent exocytic insertion of AQP1-containing vesicles mediates the secretin-induced water permeability increase in
cholangiocytes. Similar observations have been described for the
vasopressin-mediated increase in water permeability in the kidney,
which is also dependent on the integrity of the microtubular network
(27). Our results also agree with observations in renal proximal tubule
cells indicating that microtubules are involved in the insertion of
AQP1 into plasma membranes (28).
In conclusion, the results of this study suggest that secretin
facilitates osmotic water transport in cholangiocytes by inducing the
microtubule-dependent targeting of vesicles containing AQP1 water channels to the plasma membrane. We propose that this pathway provides a molecular mechanism accounting for the ability of secretin to stimulate ductal bile secretion.
FOOTNOTES ACKNOWLEDGEMENTS We thank P. Tietz, B. Vroman, and J. Tarara
for advice and assistance and D. Lubinski for secretarial help.
REFERENCES
Volume 272, Number 20,
Issue of May 16, 1997
pp. 12984-12988
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
EVIDENCE FOR A SECRETIN-INDUCED VESICULAR TRANSLOCATION OF
AQUAPORIN-1*
,,¶
Center for Basic Research in Digestive
Diseases, Departments of Internal Medicine, Biochemistry, and Molecular
Biology, Mayo Clinic and Foundation, Mayo Medical School, Rochester,
Minnesota 55905 and the § Departments of Biological
Chemistry and Medicine, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
7
M secretin), which was reversibly inhibited by the water
channel blocker HgCl2. Immunoblotting analysis of
cholangiocyte membrane fractions showed that secretin caused up to a
3-fold increase in the amount of AQP1 in plasma membranes and a
proportional decrease in the amount of the water channel in microsomes,
suggesting a secretin-induced redistribution of AQP1 from intracellular
to plasma membranes. Both the secretin-induced increase in
cholangiocyte Pf and AQP1 redistribution were
blocked by two perturbations that inhibit secretin-stimulated
exocytosis in cholangiocytes, i.e. treatment with
colchicine and exposure at low temperatures (20 and 4 °C). Our
results demonstrate that secretin increases AQP1-mediated
Pf in cholangiocytes. Moreover, our studies implicate the microtubule-dependent vesicular translocation
of AQP1 water channels to the plasma membrane, a mechanism that appears to be essential for secretin-induced ductal bile secretion and suggests
that AQP1 can be regulated by membrane trafficking.
6 M secretin (Peninsula Laboratories,
Belmont, CA); (b) for 1 h at 37 °C in the presence
of 50 µM colchicine or lumicolchicine (Sigma) and then
for an additional 15 min in the presence of 0 or 107
M secretin; (c) for 30 min at 37, 20, or 4 °C
and then for an additional 15 min in the presence of 0 or
107 M secretin at these temperatures.
7 M secretin treatment.
Pf values of cholangiocytes treated with several
doses of secretin are summarized in Fig. 1B. The effect of
secretin on cholangiocyte Pf was
dose-dependent, and Pf increased with
increasing concentrations of secretin up to 107
M (~60%); 106 M failed
to further stimulate Pf. Average cholangiocyte volume (in isotonic media) was not affected by any of the doses of
secretin used. As shown in Fig. 1C, the 107
M secretin-induced increase of cholangiocyte
Pf was inhibited by the known water channel blocker,
HgCl2, and was restored with the sulfhydryl reagent
2-mercaptoethanol (20). Similar results were seen with
108-106 M secretin (data not
shown).
Fig. 1.
Effect of secretin (SE) on the
osmotic water transport in isolated rat cholangiocytes. A,
time course of the osmotic swelling of cholangiocytes. Cells were
incubated at 37 °C for 15 min in the presence of 0 or
107 M secretin, cooled at 4 °C, and
exposed to 30 mosM hypotonic buffer at time zero.
B, membrane water permeability (Pf) of
cholangiocytes incubated in the presence of 0-106
M secretin at 37 °C for 15 min. Pf
was calculated from data of cholangiocyte swelling in 30 mosM buffer. *, p < 0.05 compared with 0 M secretin (Student's t test). C,
effect of HgCl2 on the secretin-induced increase in
cholangiocyte Pf. Cells were incubated at 37 °C
for 15 min in the presence of 0 or 107 M
secretin and cooled at 4 °C. Before the water transport assay, they
received no further treatment, or they were treated with 0.3 mM HgCl2 for 5 min or 0.3 mM
HgCl2 for 5 min followed by 10 min with 5 mM
2-mercaptoethanol. *, p < 0.05 compared with
HgCl2 or +HgCl2 + me (Student's t
test). Black bar, HgCl2; gray bar, +HgCl2; white bar, HgCl2 + 2-mercaptoethanol. All the data shown are mean ± S.E. of
measurements from 15 to 62 cholangiocytes in each experimental
group.
[View Larger Version of this Image (16K GIF file)]
Fig. 2.
Effect of secretin (SE) on the
amount of AQP1 protein in cholangiocyte membranes. A,
representative immunoblot for AQP1 on plasma and microsomal membrane
fractions. Cells were incubated in the absence () or presence (+) of
107 M secretin, and cholangiocyte membrane
fractions were prepared as described under "Materials and Methods."
E, erythrocyte plasma membranes (positive control);
H, hepatocyte plasma membranes (negative control). Each
lane was loaded with 10 µg of protein for cholangiocyte membrane fractions and hepatocyte plasma membranes and 1 µg for erythrocyte plasma membranes. B, densitometric analysis of
four separate experiments expressed in arbitrary units as mean ± S.E. *, p < 0.01 for secretin effect (Student's
t test).
[View Larger Version of this Image (26K GIF file)]
-lumicolchicine), as well as incubation at 20 and
4 °C, markedly inhibited the increase in plasma membranes and the
decrease in microsomes of AQP1 protein induced by secretin (see Fig.
3, A and B, and Fig.
4, A and B). These two
perturbations also selectively blocked the secretin-induced increase in
cholangiocyte Pf (Figs. 3C and
4C).
Fig. 3.
Effect of colchicine on the secretin-induced
redistribution of AQP1 and the increase in cholangiocyte water
permeability. A, representative immunoblot for AQP1 on
plasma and microsomal membrane fractions. Cells were incubated for
1 h at 37 °C in the presence of 50 µM colchicine,
lumicolchicine, or vehicle and then for an additional 15 min in the
absence () or presence (+) of 107 M
secretin. Membranes were prepared as described under "Materials and
Methods." Ten µg of protein were loaded in each lane.
B, densitometric analysis of three separate experiments
expressed as percent change induced by secretin (mean ± S.E.). *,
p < 0.05 compared with control (Student's
t test). C, membrane water permeability
(Pf) of cholangiocytes treated as mentioned above.
Pf was calculated from data of cholangiocyte
swelling in 30 mosM buffer. Black bar, control;
gray bar, lumicolchicine; white bar, colchicine. Data are mean ± S.E. from 15 to 35 cholangiocytes in each
experimental group. *, p < 0.05 compared with
corresponding secretin values (Student's t test).
[View Larger Version of this Image (17K GIF file)]
Fig. 4.
Effect of low temperature incubation on the
secretin-induced redistribution of AQP1 and the increase in
cholangiocyte water permeability. A, representative
immunoblot for AQP1 on plasma and microsomal membrane fractions. Cells
were incubated at either 37, 20, or 4 °C for 30 min and then for an
additional 15 min in the absence () or presence (+) of
107 M secretin. Membranes were prepared as
described under "Materials and Methods." Ten µg of protein were
loaded in each lane. B, densitometric analysis of
three separate experiments expressed as percent change induced by
secretin (mean ± S.E.). *, p < 0.05 compared
with control (Student's t test). C, membrane
water permeability (Pf) of cholangiocytes treated as
mentioned in panel A. Pf was calculated
from data of cholangiocyte swelling in 30 mosM buffer.
Black bar, 37 °C; gray bar, 20 °C;
white bar, 4 °C. Data are mean ± S.E. from 15 to 35 cholangiocytes in each experimental group. *, p < 0.05 compared with corresponding secretin values (Student's t
test).
[View Larger Version of this Image (16K GIF file)]
channels, which would operate in parallel with an apical
Cl/HCO3. Although the
actual solutes responsible for the osmotically driven ductal water
secretion are unknown, HCO3 as well as
Cl are currently considered likely to be involved (1, 2). Secretin-induced bile secretion has also been shown by morphologic techniques to be associated with a decrease in cytoplasmic vesicles (8), which was interpreted as reflecting exocytic insertion into
cholangiocyte plasma membrane (10). Thus, these observations support
the occurrence of an exocytic process involved in secretin-induced ductal water secretion. In line with these observations, the results of
this study indicate that secretin enhances cholangiocyte
Pf by inducing the exocytic insertion of AQP1 into
cholangiocyte plasma membranes. Although the precise cellular
mechanisms by which secretin mediates this exocytic translocation of
AQP1 require additional study, they are likely to overlap with
processes that modulate, via a cyclic AMP cascade, the trafficking
of the vasopressin-regulated water channel AQP2 in the kidney and the
insulin-sensitive glucose transporter GLUT 4 in adipocytes and muscle
cells (11).
7 M; increasing the concentration to
106 M failed to further increase
Pf (Fig. 1B), suggesting that
autoinhibition is activated at this concentration, a phenomenon also
reported for vasopressin-induced water permeability in the kidney
(23).
¶
To whom correspondence should be addressed: Center for Basic
Research in Digestive Diseases, Mayo Clinic, 200 First St. SW, Rochester, MN 55905. Tel.: 507-284-1006; Fax: 507-284-0762; E-mail: larusso.nicholas{at}Mayo.edu.
1
The abbreviations used are: AQP1, aquaporin-1;
Pf, membrane water permeability.
2
N. F. LaRusso, unpublished data.
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
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T. Ma, S. Jayaraman, K. S. Wang, Y. Song, B. Yang, J. Li, J. A. Bastidas, and A. S. Verkman Defective dietary fat processing in transgenic mice lacking aquaporin-1 water channels Am J Physiol Cell Physiol, January 1, 2001; 280(1): C126 - C134. [Abstract] [Full Text] [PDF]
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 N. M. Sherwood, S. L. Krueckl, and J. E. McRory The Origin and Function of the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)/Glucagon Superfamily Endocr. Rev., December 1, 2000; 21(6): 619 - 670. [Abstract] [Full Text]
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 R. M. Smith, B. Baibakov, Y. Ikebuchi, B. H. White, N. A. Lambert, L. K. Kaczmarek, and S. S. Vogel Exocytotic Insertion of Calcium Channels Constrains Compensatory Endocytosis to Sites of Exocytosis J. Cell Biol., February 21, 2000; 148(4): 755 - 768. [Abstract] [Full Text] [PDF]
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T. Ma and A S Verkman Aquaporin water channels in gastrointestinal physiology J. Physiol., June 1, 1999; 517(2): 317 - 326. [Abstract] [Full Text] [PDF]
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R. A. Marinelli, P. S. Tietz, L. D. Pham, L. Rueckert, P. Agre, and N. F. LaRusso Secretin induces the apical insertion of aquaporin-1 water channels in rat cholangiocytes Am J Physiol Gastrointest Liver Physiol, January 1, 1999; 276(1): G280 - G286. [Abstract] [Full Text] [PDF]
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 K. Ishibashi and S. Sasaki The Dichotomy of MIP Family Suggests Two Separate Origins of Water Channels Physiology, June 1, 1998; 13(3): 137 - 142. [Abstract] [Full Text] [PDF]
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F. Garcia, A. Kierbel, M. C. Larocca, S. A. Gradilone, P. Splinter, N. F. LaRusso, and R. A. Marinelli The Water Channel Aquaporin-8 Is Mainly Intracellular in Rat Hepatocytes, and Its Plasma Membrane Insertion Is Stimulated by Cyclic AMP J. Biol. Chem., April 6, 2001; 276(15): 12147 - 12152. [Abstract] [Full Text] [PDF]
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S.-J. Cho, A. K. M. A. Sattar, E.-H. Jeong, M. Satchi, J. A. Cho, S. Dash, M. S. Mayes, M. H. Stromer, and B. P. Jena Aquaporin 1 regulates GTP-induced rapid gating of water in secretory vesicles PNAS, April 2, 2002; 99(7): 4720 - 4724. [Abstract] [Full Text] [PDF]
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R. B. Doctor, R. Dahl, L. Fouassier, G. Kilic, and J. G. Fitz Cholangiocytes exhibit dynamic, actin-dependent apical membrane turnover Am J Physiol Cell Physiol, May 1, 2002; 282(5): C1042 - C1052. [Abstract] [Full Text] [PDF]
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 P. M. T. Deen, B. W. M. Van Balkom, P. J. M. Savelkoul, E.-J. Kamsteeg, M. Van Raak, M. L. Jennings, T. R. Muth, V. Rajendran, and M. J. Caplan Aquaporin-2: COOH terminus is necessary but not sufficient for routing to the apical membrane Am J Physiol Renal Physiol, February 1, 2002; 282(2): F330 - F340. [Abstract] [Full Text] [PDF]
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