INVITED REVIEW
Cl-channel activation is necessary for stimulation of Na transport
in adult alveolar epithelial cells
Scott M.
O'Grady1,
Xinpo
Jiang1, and
David
H.
Ingbar2
1 Departments of Physiology and Animal Science,
University of Minnesota, St. Paul 55108; and
2 Department of Medicine, University of Minnesota,
Minneapolis, Minnesota 55455
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ABSTRACT |
In this review, we discuss evidence that supports the
hypothesis that adrenergic stimulation of transepithelial Na absorption across the alveolar epithelium occurs indirectly by activation of
apical Cl channels, resulting in hyperpolarization and an increased driving force for Na uptake through amiloride-sensitive Na channels. This hypothesis differs from the prevailing idea that
adrenergic-receptor activation increases the open probability of
Na channels, leading to an increase in apical membrane Na
permeability and an increase in Na and fluid uptake from the alveolar
space. We review results from cultured alveolar epithelial cell
monolayer experiments that show increases in apical membrane Cl
conductance in the absence of any change in Na conductance after
stimulation by selective
-adrenergic-receptor agonists. We also
discuss possible reasons for differences in Na-channel regulation in
cells grown in monolayer culture compared with that in dissociated
alveolar epithelial cells. Finally, we describe some preliminary in
vivo data that suggest a role for Cl-channel activation in the process
of amiloride-sensitive alveolar fluid absorption.
ion transport; epithelial sodium channel; cystic fibrosis
transmembrane conductance regulator; terbutaline
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INTRODUCTION |
BASOLATERAL ADDITION of the selective
2-agonist terbutaline increases amiloride-sensitive
short-circuit current (Isc) and net Na absorption
as determined by transepithelial flux experiments across adult rat
alveolar epithelial cells under short-circuit conditions (4, 9, 17,
18). The time course of terbutaline action on Isc
exhibited an initial rapid decrease in current followed by a
time-dependent increase in Isc that reached a new
steady-state plateau that was ~40% greater than the basal
Isc (4). This sustained increase in current was
inhibited by the apical addition of amiloride. The magnitude of the
amiloride-sensitive Isc observed after terbutaline
stimulation closely agreed with the terbutaline-stimulated net Na flux
across the monolayer, providing strong support for the conclusion that
terbutaline increases transepithelial Na absorption and that
amiloride-sensitive Na channels are involved in the process. In a
subsequent study (9), terbutaline was shown to increase net
transepithelial Cl absorption as reflected by an increase in the
apical-to-basolateral unidirectional Cl flux. The flux experiments were
performed under short-circuit conditions (transepithelial potential
held at 0 mV) with symmetric physiological saline solutions bathing
both the apical and basolateral surfaces of the epithelium. Under these
conditions, the increase in Cl transport must have resulted from
activation of a transcellular pathway for Cl absorption. Thus
terbutaline stimulates active NaCl absorption across monolayers of
adult rat alveolar epithelial cells, but the mechanisms responsible for
transcellular Cl transport were not identified in these earlier investigations.
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CHLORIDE-CHANNEL ACTIVATION AND REGULATION OF ALVEOLAR SODIUM
TRANSPORT |
Terbutaline and cAMP activate apical membrane Cl channels in
cultured alveolar epithelial cells. In a recent study, Jiang et al. (8) demonstrated that the addition of 2 µM terbutaline to the basolateral surface of cultured adult rat
alveolar epithelial cells bathed on both sides with DMEM-Ham's F-12
medium produced changes in Isc that were similar to
those previously reported by Cheek et al. (4). Figure
1A shows the biphasic effects of terbutaline on Isc, beginning with a rapid decrease
in current followed by a time-dependent increase in
Isc that was blocked by amiloride. The initial
decrease in Isc was clearly apparent (but smaller
in magnitude) when the monolayer was pretreated with apical amiloride,
but no secondary increase in current was detected in the presence of
amiloride (Fig. 1B). Cl replacement experiments abolished the
initial decrease in Isc produced by the basolateral addition of terbutaline, and no significant increase in
amiloride-sensitive current was detected in the absence of Cl (Fig.
2). Similar results were obtained when
monolayers were treated with 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP).
These results suggested the presence of a terbutaline- and
cAMP-activated electrogenic Cl transport pathway that could potentially
mediate Cl absorption across the monolayer.

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Fig. 1.
Representative short-circuit current (Isc) tracings
showing effects of basolateral administration of terbutaline (2 µM)
on Isc with and without pretreatment with apical
amiloride (20 µM). Monolayer filters (4.5 cm2) were
mounted in Ussing chambers and bathed on both apical and basolateral
sides with identical serum-free DMEM-Ham's F-12 medium. A:
addition of terbutaline produced a rapid decrease in
Isc followed by a slow increase back to initial
Isc. Addition of amiloride blocked most of
remaining Isc. B: in presence of amiloride,
addition of terbutaline produced a rapid sustained decrease in
Isc without a secondary recovery phase.
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Fig. 2.
Representative Isc tracings showing effects of
basolateral administration of terbutaline (2 µM) on
Isc under Cl -free conditions.
Monolayers (4.5 cm2) were mounted in Ussing chambers and
bathed with identical Cl -free Ringer solution on
both apical and basolateral sides. No response was produced by
terbutaline, whereas addition of amiloride (20 µM) to apical solution
produced a sustained decrease in Isc.
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It is worth noting that comparison of current traces from monolayers
bathed in serum-free DMEM-Ham's F-12 medium and Cl-free saline
solution indicates a reduction in basal Isc under
Cl-free conditions (Fig. 2). This reduced basal current is due to the absence of amino acids (normally present in DMEM-Ham's F-12 medium) and is not the result of basal Cl secretion. Replacement of DMEM-Ham's F-12 medium with Cl-containing Ringer solution produces a decrease in
basal Isc similar in magnitude to that observed in
Cl-free solution. Addition of the same free amino acids present in
DMEM-Ham's F-12 medium to the apical solution produces a
concentration-dependent increase in basal current for monolayers bathed
in either Cl-containing Ringer solution or Cl-free solution. This
result is consistent with the presence of an electrogenic amino acid
cotransport system in the apical membrane that contributes to the basal
Isc (8).
To characterize terbutaline-regulated transport pathways present in the
apical membrane, we used the pore-forming antibiotic amphotericin to
perforate the basolateral membrane, thus eliminating it as a resistive
barrier to the movement of monovalent ions. The basolateral and apical
surfaces of the monolayer were bathed with either intracellular
solution (in mM: 120 potassium methanesulfonic acid, 10 mM NaCl, 20 mM
KHCO3, 0.7 MgSO4, 0.3 KH2PO4, 3 mM calcium gluconate, and 30 mannitol) or DMEM-Ham's F-12 medium, respectively. The apical membrane
voltage was stepped through a series of command potentials ranging
between +70 and
70 mV in 10-mV increments before and after
treatment with either terbutaline or 8-CPT-cAMP. The current-voltage
relationships for the terbutaline-activated and cAMP-activated
conductances (Fig. 3A) were nearly
linear, and the reversal potentials were
28.4 ± 2.7 and
26.3 ± 2.5 mV, respectively. To confirm that Cl was the
permeant ion, increasing the Cl concentration in the intracellular
solution from 10 to 20 to 35 mM produced a shift in reversal potential
to more depolarized voltages as the Cl concentration gradient
decreased, indicating that Cl was the current-carrying ion (Fig.
3B). The anion selectivity of the terbutaline-activated current
was examined by performing a series of bi-ionic experiments with Br, I,
and thiocyanate and measuring the shift in reversal potential produced
in the presence of each of these replacement anions in the apical
solution. The selectivity sequence was found to be thiocyanate > Br > Cl > I, similar to that previously reported for the cystic
fibrosis transmembrane conductance regulator (CFTR) (1). As a control
for the bi-ionic experiments, the current-voltage relationship for the
terbutaline-activated current was measured under symmetrical Cl
concentration conditions in the presence of an outwardly directed K
concentration gradient and an inwardly directed Na concentration
gradient. The reversal potential for the terbutaline-activated current
was not significantly different from zero, again indicting that Cl was
the current-carrying ion and that terbutaline does not alter apical
membrane Na or K conductance. Finally, three known Cl-channel blockers
[5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB),
glibenclamide, and diphenylamine-2-carboxylic acid (DPC)]
produced a concentration-dependent block of the terbutaline-activated current with the following order of potency: NPPB
(IC50 = 12 mM) > glibenclamide
(IC50 = 110 mM) > DPC (IC50 = 640 mM) (Fig.
4).

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Fig. 3.
Current-voltage relationships for terbutaline- and
8-(4-chloro-phenylthio)-cAMP (8-CPT-cAMP)-activated
conductance in apical membrane. Experiments were performed with
amphotericin-perforated monolayers (4.5 cm2) mounted in
Ussing chambers and bathed with potassium methanesulfonic acid
(KMeSO4)-Ringer solution on basolateral side and serum-free
DMEM-Ham's F-12 medium on apical side. A: current-voltage plot
for terbutaline- and 8-CPT-cAMP-activated currents, with mean reversal
potentials of 28.42 ± 2.68 and 26.32 ± 2.50 mV,
respectively. Terbutaline (2 µM) and 8-CPT-cAMP (100 mM) were applied
to basolateral bathing solution after pretreatment of monolayers with
apical amiloride (20 µM). B: increasing basolateral Cl
concentration ([Cl]i) produced a shift in
terbutaline-sensitive reversal potential. Experiments were performed
with amphotericin-perforated monolayers mounted in Ussing chambers and
bathed with KMeSO4-Ringer solution on basolateral side and
serum-free DMEM-Ham's F-12 medium on apical side. Changes in
[Cl]i were achieved by replacing
KMeSO4 with equimolar KCl. Terbutaline (2 µM) was applied
to basolateral bathing solution after pretreatment of monolayers with
apical amiloride (20 µM). Reversal potentials were plotted against
log of basolateral [Cl]i values. Linear
regression analysis was used to fit data (R = 0.983).
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Fig. 4.
Effects of Cl-channel blockers on terbutaline-activated current.
Experiments were performed with amphotericin-perforated monolayers (4.5 cm2) mounted in Ussing chambers and bathed with
KMeSO4-Ringer solution on basolateral side and serum-free
DMEM-Ham's F-12 medium on apical side. Monolayer voltage was clamped
at 0 mV. 5-Nitro-2-(3-phenylpropylamino)benzoic acid (NPPB),
glibenclamide, and diphenylamine-2-carboxylic acid (DPC) were added to
apical solution. A: representative tracing of effect of apical
glibenclamide on terbutaline-activated current. B:
concentration-response relationship for NPPB, glibenclamide, and DPC
inhibition of terbutaline-sensitive current. IC50 values
for NPPB, glibenclamide, and DPC were 12, 110, and 640 µM,
respectively.
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Recently, cAMP-activated Cl currents were observed in monolayer
cultures of adult rabbit alveolar epithelial cells (13). Stimulation
with cAMP increased the Isc. This response was
blocked by basolateral treatment with bumetanide, suggesting that cAMP stimulates Cl secretion. In contrast to these results from rabbit monolayers, terbutaline- and cAMP-stimulated Isc
responses in adult rat alveolar cell monolayers were unaffected by
basolateral bumetanide treatment and the direction of the current
response was not consistent with stimulation of Cl secretion.
Terbutaline and cAMP do not directly increase the
amiloride-sensitive Na conductance. An interesting observation from
the Cl replacement experiments shown in Fig. 2 was the absence of any
increase in amiloride-sensitive Isc after treatment
with terbutaline. Similar results were obtained when monolayers were
stimulated with 8-CPT-cAMP under Cl-free conditions. These results
suggested that terbutaline and cAMP do not directly activate apical
membrane Na channels. To test this further, we again used amphotericin to perforate the basolateral membrane so that we could investigate the
effects of terbutaline on apical membrane Na conductance. The
basolateral and apical surfaces of the monolayer were bathed with
intracellular solution and DMEM-Ham's F-12 medium, respectively, and
the apical membrane voltage was clamped at 0 mV. Under these conditions, basolateral addition of terbutaline produced a decrease in
current without the secondary increase that was previously observed in
nonpermeable monolayers (Fig. 5). The lack
of an increase in amiloride-sensitive current after stimulation with
terbutaline again supported the conclusion that amiloride-sensitive Na
channels were not activated in response to
-adrenergic stimulation.
In addition, examination of the current-voltage relationship for amiloride-sensitive Na channels in the apical membrane (Fig.
6) showed that the reversal potential was
46.5 mV, indicating high selectivity for Na over K (12.5:1), and no
significant difference in either the conductance or reversal potential
could be detected after terbutaline stimulation. The results shown in
Fig. 6 represent difference currents calculated from the
current-voltage relationships measured before and after amiloride
treatment. Thus the results of these experiments support the conclusion
that the increase in Na absorption produced by terbutaline is not the
result of direct activation of amiloride-sensitive Na channels present
in the apical membrane.

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Fig. 5.
Representative Isc tracings showing effects of
basolateral addition of terbutaline (2 µM) followed by apical
addition of amiloride (20 µM; A) or apical addition of
amiloride (20 µM) followed by basolateral addition of terbutaline (2 µM; B). Experiments were performed with
amphotericin-perforated monolayers (4.5 cm2) mounted in
Ussing chambers and bathed with KMeSO4-Ringer solution on
basolateral side and serum-free DMEM-Ham's F-12 medium on apical side.
Voltage across monolayers was clamped at 0 mV. C:
terbutaline (T)-activated and amiloride (A)-sensitive current responses
obtained from amphotericin-perforated monolayers voltage clamped at 0 mV. Pretreatment with amiloride did not significantly affect magnitude
of terbutaline-activated current (15.29 ± 3.38 µA and 14.06 ± 4.26 µA). In addition, pretreatment with terbutaline did not
significantly affect amiloride-sensitive current (7.63 ± 0.92 and
6.63 ± 1.23 µA).
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Fig. 6.
Current-voltage relationship for apical membrane amiloride-sensitive Na
conductance. Experiments were performed with amphotericin-perforated
monolayers (4.5 cm2) mounted in Ussing chambers and bathed
with KMeSO4-Ringer solution on basolateral side and
serum-free DMEM-Ham's F-12 medium on apical side. Amiloride (20 µM)
was applied to apical bathing solution, and terbutaline (2 µM) was
applied to basolateral bathing solution. Mean reversal potentials for
amiloride-sensitive current in absence (control) and presence of
terbutaline were 46.47 ± 3.44 and 49.58 ± 4.29 mV, respectively.
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Role of Cl-channel activation in stimulation of transepithelial Na
absorption. We propose the following model to explain
-adrenergic stimulation of Na and Cl absorption in cultured adult
rat alveolar epithelial cells (Fig.
7). Both Na and Cl channels
are present in the apical membrane, and in the absence of adrenergic
agonists, Na channels are constitutively open and Cl channels are
closed. Na influx through amiloride-sensitive Na channels maintains the apical membrane at a voltage that is more depolarized than the reversal
potential of apical membrane Cl channels. Adrenergic-receptor stimulation with terbutaline or treatment with cell-permeant analogs of
cAMP activate Cl channels without directly increasing apical membrane
Na conductance. This increase in apical membrane Cl permeability rapidly decreases the Isc after adrenergic
stimulation, consistent with Cl influx across the apical membrane in
response to an inwardly directed electrochemical gradient. Electrogenic
Cl influx by this mechanism hyperpolarizes the apical membrane and
increases the driving force for Na uptake through amiloride-sensitive
Na channels. This is consistent with the time-dependent,
amiloride-inhibitable increase in Isc that follows
the rapid decrease in current produced by terbutaline. This secondary
phase of the terbutaline response is eliminated if the monolayers are
pretreated with amiloride and is not observed at all in
amphotericin-permeable monolayers where hyperpolarization is prevented
by voltage clamping the apical membrane at 0 mV. Thus stimulation of
amiloride-sensitive Na absorption by terbutaline or 8-CPT-cAMP is
dependent on an increase in driving force produced by electrogenic Cl
uptake mediated by apical membrane Cl channels. The idea that Cl
absorption can involve apical Cl channels serving as uptake pathways
for Cl was first proposed in human sweat duct epithelial cells where
activation of CFTR resulted in Cl influx across the apical membrane
(16). More recently, CFTR was shown to directly mediate Cl absorption
and transepithelial fluid absorption in cultured bovine tracheal
epithelial cells (20).

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Fig. 7.
Cell model showing proposed mechanisms for Na and Cl transport across
adult rat alveolar epithelial cells. PKA, protein kinase A, AC,
adenylyl cyclase; G, G protein.
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An interesting result from our studies of alveolar epithelial cell
monolayers is that terbutaline and 8-CPT-cAMP do not increase apical
membrane Na conductance. This contrasts with the results of previous
experiments with dissociated adult rat alveolar epithelial cells and
fetal alveolar epithelial cells where cAMP and adrenergic stimulation
increase the open probability of amiloride-sensitive Na channels
without changes in single-channel conductance (11, 12, 19). One
possible explanation for the discrepancy between our studies and a
previous report on adult alveolar epithelial cells (12) may be related
to differences in the regulation of epithelial Na channels (ENaC) in
dissociated cells compared with cells in monolayers. Dissociated cells
lose their polarity once tight junction complexes have been disrupted.
This can alter the cell surface distribution of Na channels and
possible regulatory proteins, resulting in different responses to
second messengers such as cAMP. It is worth noting that association of
regulatory proteins with ENaC subunits may be essential for conferring
cAMP sensitivity to Na channels in epithelial cells. This idea is
supported by the observation that injection of
-ENaC,
-ENaC, and
-ENaC subunit cRNAs into Xenopus oocytes
results in expression of amiloride-sensitive Na channels that are
inhibited by protein kinase C activation but do not respond to
increases in intracellular cAMP (2).
Mechanism of terbutaline stimulation of alveolar fluid
absorption. It has been previously shown that adrenergic agonists
increase fluid absorption across the rat alveolar epithelium and that
this increase is inhibited if the lungs are infused with amiloride (5,
15, 18). This result supports the idea that stimulation of
amiloride-sensitive Na absorption establishes the necessary osmotic
driving force required for fluid removal from the alveoli (3, 6, 7,
14). The proposed mechanism to account for enhanced Na absorption is an
increase in apical membrane Na permeability resulting from
cAMP-mediated increases in the open probability of amiloride-sensitive
Na channels. We suggest that there is another potential explanation
consistent with results of our monolayer experiments with adult rat
alveolar epithelial cells. Preliminary in vivo studies of fluid
absorption in adult rats indicate that infusion of the Cl-channel
blocker NPPB into rat lungs blocks terbutaline-stimulated increases in
fluid absorption (10). Basal amiloride-sensitive fluid absorption was
unaffected by treatment with NPPB. The lack of effect of NPPB on basal
fluid absorption indicates that NPPB does not block amiloride-sensitive
Na channels and is not toxic to the alveolar epithelium under in vivo
conditions. These results suggest a role for Cl-channel activation in
increasing amiloride-sensitive fluid absorption in adult rats. At the
present time, it is not possible to confirm whether any increase in
Na-channel activation takes place under in vivo conditions so we do not
exclude the possibility that terbutaline may directly activate Na
channels under in vivo conditions as well.
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CONCLUSIONS |
The original goal of our studies with alveolar epithelial monolayers
was to understand the mechanism of adrenergic receptor-stimulated Cl absorption previously observed by Kim et al. (9) using a similar preparation of rat alveolar epithelial cells. Our experiments indicate that selective
-adrenergic-receptor agonists such as terbutaline activate apical membrane Cl channels with
functional and pharmacological properties similar to those of CFTR.
Our results indicate that adult rat alveolar epithelial cells
absorb Cl from the apical medium by a mechanism analogous to that
proposed for human sweat duct and bovine airway epithelial cells. This
mechanism is interesting in that it involves an electrogenic influx
pathway for Cl. Cl uptake is possible as a result of depolarization
produced by Na influx through amiloride-sensitive Na channels present
in the apical membrane. The mechanism for Cl efflux across the
basolateral membrane is presently unknown but may involve an
electroneutral transporter such as KCl cotransport or basolateral Cl
channels. Our results indicate that an important secondary effect of
Cl-channel activation is to increase transepithelial Na absorption. We
propose that this is due to an increase in electrical driving force for Na uptake across the apical membrane through amiloride-sensitive Na
channels and does not involve any increase in apical membrane Na
permeability. Preliminary data from in vivo experiments provide pharmacological evidence to suggest that Cl-channel activation by
terbutaline also occurs in intact adult rat lungs and that this
activation is coupled to an increase in amiloride-sensitive fluid
absorption. We suggest that activation of a transcellular pathway for
Cl absorption that couples to and enhances the rate of transepithelial
Na absorption provides an efficient mechanism for alveolar solute
absorption and increases the osmotic driving force for fluid absorption
across the alveolar epithelium.
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FOOTNOTES |
Address for reprint requests and other correspondence: S. M. O'Grady, Departments of Physiology and Animal Science, 495 Animal
Science/Veterinary Medicine Bldg., Univ. of Minnesota, St. Paul, MN
55108 (E-mail: ograd001{at}tc.umn.edu).
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