INVITED REVIEW
Mechanisms of increased Na+ transport in ATII cells by
cAMP: we agree to disagree and do more experiments
Ahmed
Lazrak1,
Vance G.
Nielsen1, and
Sadis
Matalon1,2,3
Departments of 1 Anesthesiology,
2 Physiology and Biophysics, and
3 Comparative Medicine, The University of Alabama
at Birmingham, Birmingham, Alabama 35249
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ABSTRACT |
Existing evidence supports the presence
of active transport of Na+ across the mammalian alveolar
epithelium and its upregulation by agents that increase cytoplasmic
cAMP levels. However, there is controversy regarding the mechanisms
responsible for this upregulation. Herein we present the results of
various patch-clamp studies indicating the presence of 25- to 27-pS,
amiloride-sensitive, moderately selective Na+ channels
(Na+-to-K+ permeability ratio = 7:1) located on
the apical membranes of rat alveolar type II (ATII) cells maintained in
primary culture. The addition of terbutaline to the bath solution
increased the open probability of single channels present in
cell-attached patches of ATII cells without affecting their
conductance. A similar increase in open probability was seen after the
addition of protein kinase A, ATP, and Mg2+ to the
cytoplasmic side of inside-out patches. Measurement of short-circuit
currents across confluent monolayers of rat or rabbit ATII cells
indicates that terbutaline and 8-(4-chlorophenylthio)-cAMP increase vectorial Na+ transport and activate
Cl
channels. Currently, there is a controversy as to
whether the cAMP-induced increase in Na+ transport is due
solely to hyperpolarization of the cytoplasmic side of the ATII cell
membrane due to Cl
influx or whether it results from
simultaneous stimulation of both Cl
and
Na+ conductive pathways. Additional studies are needed to
resolve this issue.
terbutaline; adenosine 3',5'-cyclic
monophosphate; alveolar type II cells; sodium channels; amiloride; patch clamp; 5-(N-ethyl-N-isopropyl)-amiloride
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INTRODUCTION |
THE EXISTENCE of active Na+ reabsorption
across the adult alveolar epithelium in vivo in a number of species,
including human, has been well documented (for a review, see Ref. 17).
In brief, plasma or normal saline containing 5% bovine serum albumin
instilled in the alveolar spaces of anesthetized animals or isolated
perfused lungs is reabsorbed within a few hours. Coinstillation of
amiloride or 5-(N-ethyl-N-isopropyl)-amiloride into the
alveolar space or injection of ouabain into the circulation
significantly decreases the rate of fluid reabsorption (16, 20, 29).
Additional insight into the nature of the transporters was derived from
electrophysiological measurements performed on alveolar type II (ATII)
cells. Patch-clamp studies (7, 30) demonstrated the presence of
nonselective and moderately selective Na+ channels in
the apical membranes of ATII cells maintained in primary
culture. Furthermore, when grown to confluence and mounted in Ussing chambers, ATII cells generate a spontaneous potential difference and short-circuit current (Isc) that are
inhibited to a large extent by amiloride and ouabain (4). Based on the results of these studies, we now believe that Na+ diffuses
passively across the ATII apical membrane, mainly through cation
channels (23), down a favorable electrochemical gradient maintained by
Na+-K+-ATPase and then are actively transported
across the basolateral membrane by the ouabain-sensitive
Na+-K+-ATPase. K+ leaves ATII
cells, driven by their favorable electrochemical gradient, through
K+ channels located in the basolateral membrane, whereas
Cl
crosses through the paracellular junctions in
response to the transepithelial potential difference.
The importance of active Na+ transport in fluid
clearance across the injured alveolar epithelium was demonstrated
by two different studies. First, instillation of phenamil, an
irreversible blocker of epithelial Na+ channels, into the
lungs of rats exposed to hyperoxia resulted in higher levels of lung
water compared with rats receiving vehicle alone (29). Second, a
positive correlation has been established between active
Na+ transport across the alveolar space of patients with
acute lung injury and the rate of resolution of noncardiogenic
pulmonary edema (18). The demonstration that Na+ transport
across the alveolar epithelium in vivo and ex vivo, as well as across
ATII cells, can be upregulated by
-agonists (2, 4, 5) has led to
speculation that these agents may be useful in limiting alveolar edema
and decreasing morbidity and mortality in patients with acute lung injury.
Presently, there is controversy concerning the mechanisms by which
-agonists such as terbutaline or lipid-soluble analogs of cAMP such
as 8-(4-chlorophenylthio)-cAMP (8-CPT-cAMP) increase Na+
transport across alveolar epithelial cells. Activation of
2-receptors, shown to be present on ATII cell surfaces
(3), generally stimulates adenylate cyclase that, in turn, increases
intracellular cAMP levels and activates Na+ channels in a
number of epithelial cells and tissues (8, 12). However,
Isc measurements across rabbit and rat ATII cells
indicate that cAMP-induced responses are considerably more complex and involve both Na+ and Cl
conductive
pathways (11, 19). Based on the results of their experiments in Ussing
chambers, Jiang et al. (11) proposed that agents that increase cAMP
activate apical cystic fibrosis transmembrane conductance regulator
(CFTR)-type Cl
channels. Because the resting
membrane potential of ATII cells is around
40 mV, stimulation of
Cl
channels will result in influx of
Cl
, hyperpolarization of the apical membrane, and
creation of a favorable driving force for increased Na+
transport. These investigators did not find any evidence of activation of Na+ channels by cAMP in their experimental model.
Herein, we present evidence indicating that increased levels of cAMP in
the ATII cell cytoplasm activate amiloride-sensitive Na+
channels. Results of patch-clamp studies convincingly show that
-agonists increase the open probability (Po) and
mean open time (
1)of amiloride-sensitive single
Na+ channels located in the apical membranes of rat ATII
cells maintained in primary culture without altering their
single-channel unitary conductance. Furthermore, protein kinase A (PKA)
in the presence of ATP phosphorylated a putative
Na+-channel protein isolated from rabbit ATII cells and
activated an amiloride-sensitive single channel when this protein was
reconstituted in planar lipid bilayers. Finally, we believe that the
results of Isc measurements across cultured rat and
rabbit ATII cells obtained from a number of laboratories (4, 19)
indicate that cAMP-stimulated vectorial Na+ transport
cannot be explained solely by activation of Cl
channels.
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SINGLE-CHANNEL RECORDINGS IN ATII CELLS: EFFECTS OF
CAMP/PKA |
Single channels with diverse biophysical properties have been detected
in ATII cells isolated from the lungs of adult rabbits, rats, and
guinea pigs (for a review, see Ref. 15). Yue et al. (30) isolated ATII
cells from the lungs of rats by elastase digestion and plated them on
fibronectin-treated coverslips for 12-24 h. In cells patched in
the cell-attached mode, single-channel currents were observed for
holding potentials between
80 and +30 mV, with a
single-channel conductance of 27 ± 3 pS in 10-15% of successful
patches (Figs. 1 and 2). The
addition of 10 µM terbutaline (a potent
2-agonist
known to increase intracellular cAMP levels) to the bath increased the
1 and Po of these channels without affecting their unitary conductance (Table
1). Pretreatment of ATII cells with
propranolol (10 µM), a
2-antagonist, obviated the
terbutaline-induced increases in Po and
1. Because ATII cells in primary culture orient
themselves so that their basal membranes are attached to the substratum
and the apical membranes are pointing upward (14), channels in excised
or cell-attached patches are likely to be located in their apical
membranes.

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Fig. 1.
Sample recordings of single-channel currents from a cell-attached patch
obtained from an alveolar type II (ATII) cell cultured for 24 h. Ionic
composition of pipette and bath solutions was (in mM) 150 sodium
glutamate, 5 HEPES, 2 CaCl2, and 1 EGTA, pH 7.2. Applied
potential difference across patch membrane was 20 mV
(extracellular side as reference). A: single-channel current
obtained under control conditions (downward deflection indicates inward
positive currents). B: single-channel current across the same
cell 5 min after terbutaline (10 µM) was added to bath solution.
[Reprinted from Yue et al. (30) with permission.]
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Fig. 2.
Current-voltage (I-V) relationships for single-channel
currents obtained from ATII cells patched in cell-attached mode before
[control (cont)] and 5 min after addition of 10 µM
terbutaline (Terb) to bath solution. Ionic composition of pipette and
bath solutions was (in mM) 150 sodium glutamate, 5 HEPES, 2 CaCl2, and 1 EGTA, pH 7.2. Lines were fitted through data
points with linear regression and extrapolated to 0 current. Notice
absence of currents for applied potential differences exceeding +30 mV
(extracellular side as reference). Values are means ± SE; n = 7. In most cases, SE was smaller than width of symbols.
[Reprinted from Yue et al. (30) with permission.]
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Table 1.
Po and 1 of single channels in
cell-attached and inside-out patches of rat ATII cells maintained in
primary culture
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Single-channel currents with a conductance of 25 ± 2 pS and
Na+-to-K+ permeability ratio
(PNa/PK) of 7:1 (Figs.
3-5)
were also recorded across 50% of ATII cells patched in the inside-out
mode (30). The addition of 1 µM amiloride or
5-(N-ethyl-N-isopropyl)-amiloride to the pipette
solution (150 mM sodium glutamate) blocked single-channel activity
almost completely. The addition of 250 U/ml of PKA, 1 mM ATP, and 5 mM
MgCl2 to the bath solution (150 mM sodium glutamate) increased the single-channel
1 and
Po without altering the unitary conductance (Figs.
3-5, Table 1). The observed increase in Po
with PKA may have been brought about by direct phosphorylation of
Na+-channel proteins or phosphorylation of cytoskeletal
proteins such as actin, ankyrin, spectrin, or fondrin interacting
with Na+-channel proteins (22, 26).

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Fig. 3.
Sample recordings of single channels recorded across an ATII cell
patched in inside-out mode. Ionic composition of pipette solution
was (in mM) 150 sodium glutamate, 5 HEPES, 2 CaCl2, and 1 EGTA, pH 7.2, and that of bath solution was (in mM) 150 sodium
glutamate, 5 HEPES, and 1 EGTA, pH 7.2. Applied potential difference
across patch membrane was 60 mV (extracellular side as
reference). A: single-channel current recorded under control
conditions. B: single-channel current obtained across the same
cell 5 min after addition of 250 U/ml of protein kinase A (PKA), 1 mM
ATP, and 5 mM MgCl2 to bath (cytoplasmic) side of patch.
[Reprinted from Yue et al. (30) with permission.]
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Fig. 4.
I-V relationships for inside-out patches in ATII cells
recorded with symmetrical and nonsymmetrical conditions. Ionic
compositions for symmetrical solutions were (in mM) 150 sodium
glutamate, 5 HEPES, 2 CaCl2, and 1 EGTA, pH 7.2, for
pipette and 150 sodium glutamate, 5 HEPES, and 1 EGTA, pH 7.2, for
bath. For nonsymmetrical solutions, sodium glutamate in bath was
replaced by 150 mM potassium glutamate.
PNa+/PK+,
Na+-to-K+ permeability ratio. Values are
means ± SE; n = 6 cells. In most cases, SE was
smaller than width of symbols. Lines were fitted through points by
linear regression. [Reprinted from Yue et al. (30) with
permission.]
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Fig. 5.
Current amplitudes for inside-out patches shown in Fig. 3. Small shift
in conductance after addition of PKA (250 U/ml), ATP (1 mM), and
MgCl2 (5 mM) was not significant (see Table 1).
[Reprinted from Yue et al. (30) with permission.]
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Nonselective (PNa/PK = 1),
voltage-independent, Ca+2-activated [intracellular
Ca2+ concentration > 0.1 mM] cation channels with a
conductance of 20.4 pS in symmetric NaCl (150 mM) solutions have also
been identified in rat ATII cells patched in the inside-out mode after
culture on collagen-coated coverslips for 24 and 72 h (7). The effects of cAMP/PKA on these channels have not been reported. However, the
biophysical properties of these Ca+2-activated channels are
almost identical to those recorded in fetal distal lung epithelial
cells (21). Marunaka et al. (13) and Tohda et al. (28)
reported that the addition of 10 µM terbutaline to the bath solution
of fetal distal lung epithelial cells, patched in the cell-attached
mode, increased the Po of the
Ca+2-activated, nonselective cation channels. Furthermore,
in the presence of brefeldin A, terbutaline did not alter the density of the Ca+2-activated cation channel, indicating that
terbutaline may promote the trafficking of this cation channel to
the apical cell surface (9).
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RECONSTITUTION OF IMMUNOPURIFIED ATII CELL
NA+-CHANNEL PROTEIN INTO PLANAR LIPID
BILAYERS: EFFECTS OF PKA |
A putative Na+-channel protein was isolated from freshly
isolated rabbit ATII cells with ion-exchange chromatography followed by
immunoaffinity purification in a column coated with a polyclonal antibody raised against purified bovine renal Na+-channel
protein. The ATII Na+-channel protein consists of two
peptides with molecular masses of ~130 and 70 kDa (25). When this
protein was reconstituted in lipid bilayers, single-channel currents
with linear current-voltage relationships and a unitary conductance of
25 pS were seen (25), in agreement with what was observed in rat ATII
cells patched in the cell-attached or inside-out modes (10, 30). The
addition of PKA and ATP to the presumed cytoplasmic side of the bilayer increased the Po from 0.40 ± 0.14 to 0.8 ± 0.12 without altering the channel unitary conductance. In additional
studies, Berdiev et al. (1) showed that PKA phosphorylated both the
135- and 70-kDa polypeptides of the immunopurified ATII
Na+-channel protein. Studies in A6 cells have shown that
PKA phosphorylates a subunit of the Na+-channel protein and
that the level of phosphorylation correlates with vectorial
Na+ transport (24).
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CHANGES IN ISC ACROSS ATII CELL MONOLAYERS BY
CAMP |
Patch-clamp measurements provide definitive evidence for the existence
of ion channels on cell membranes and considerable insight as to the
factors responsible for their regulation. There is considerable
interest in correlating these findings with macroscopic measurements of
Na+ transport across confluent ATII monolayers. Jiang et
al. (11) isolated and purified ATII cells from the lungs of adult rats and cultured them on large Transwell membrane filters using serum-free medium until they formed confluent monolayers. Six days later, ATII
cells developed large Isc values, 60% of which
were inhibited by 10 µM amiloride. The basolateral addition of
terbutaline (2 µM) resulted in a rapid decrease in
Isc followed by a gradual recovery to its baseline
value (Fig. 6). When amiloride was added before terbutaline, Isc decreased but failed to
return to its baseline value. Finally, when ATII monolayers were bathed
in a Cl
-free solution, the response to terbutaline
was almost completely abolished. Based on these findings, they proposed
that terbutaline stimulated Cl
absorption through an
apical Cl
conductance. The Cl
influx hyperpolarized the cell membrane, increasing the driving force
for Na+ entry. Thus their measurements indicate that
terbutaline stimulates Na+ transport without directly
activating apical Na+ channels.

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Fig. 6.
Representative short-circuit current (Isc) tracings
showing effects of Terb (2 µM) added into basolateral compartment of
an Ussing chamber containing confluent monolayers of rat ATII cells in
presence and absence of apical amiloride (Amil). [Redrawn from
Jiang et al. (11) with permission.]
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However, results from other laboratories cannot be explained by this
model. For example, Cheek et al. (4) showed that the addition of
terbutaline to the basolateral bath of an Ussing chamber containing
confluent monolayers of rat ATII cells resulted in a transient decrease
in Isc followed by a gradual increase to steady-state levels, surpassing the baseline (Fig.
7). About 80% of
Isc after terbutaline stimulation was abolished by
the addition of 10 µM amiloride to the apical compartment. The
initial decrease in Isc is consistent with the
findings of Jiang et al. (11) and is most likely due to activation of a
Cl
conductance. However, Jiang et al.'s model
cannot account for the increase in Isc
above its initial value after terbutaline stimulation. Instead, Cheek
et al.'s (4) data suggest that terbutaline stimulates
Na+-conductive pathways secondary to an increase in cAMP.
Indeed, this group reported that terbutaline stimulated the net
apical-to-basolateral flux of 22NaCl, and the magnitude of
stimulation was similar to the steady-state increase in
Isc. An important experiment that needs to be done is to repeat these measurements in monolayers pretreated with amiloride
and show that, under those conditions, the response of
Isc to terbutaline is blunted.

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Fig. 7.
Isc responses of rat ATII cell monolayers to Terb
(100 µM) added to basolateral compartment of an Ussing chamber. At
indicated time, Amil (10 µM) was added into apical compartment.
[Modified from Cheek et al. (4) with permission.]
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In another study, Nielsen et al. (19) assessed the effects of forskolin
and 8-CPT-cAMP on the Isc of rabbit ATII cells
grown to form tight confluent monolayers. Either forskolin (10 µM) or 8-CPT-cAMP (100 µM) produced an early biphasic change in the
Isc followed by a slow steady-state increase to a
value that was 3.4 ± 0.2 µA/cm2 higher than baseline,
in agreement with the data of Cheek et al. (4) (Fig.
8). In addition, Nielsen et al. (19) showed that the addition of forskolin to monolayers pretreated with amiloride resulted in a sustained increase in Isc. There are
several explanations for these findings: first, forskolin may have
reversed the effect of amiloride; second, it may have stimulated
Na+ absorption across nonamiloride-sensitive pathways; and
third, it may have induced Cl
secretion across
cAMP-activated Cl
channels. In any event, their data
cannot be explained by the model of Jiang et al. (11). Current
experiments in a number of laboratories are attempting to identify the
mechanisms involved and the factors that may reconcile these apparently
contradictory results.

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Fig. 8.
Isc recordings from ATII cell monolayers mounted in
Ussing chambers. Addition of forskolin (Forsk; 10 µM) increases
Isc either before (A) or after (B)
Amil (10 µM) administration. Further addition of cystic fibrosis
transmembrane conductance regulator channel blocker glibenclamide
(Glib; 200 µM) and/or loop diuretic bumetanide (Bumet; 100 µM)
decreased Forsk-mediated Isc. Results represent a
typical experiment. [Modified from Nielsen et al. (19) with
permission.]
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CONCLUSIONS AND UNANSWERED QUESTIONS |
Measurement of single-channel activity in cell-attached and inside-out
patches of dispersed ATII cells maintained in primary culture provides
strong support for the hypothesis that agents that increase cAMP
increase the activity of moderately selective, amiloride-sensitive
Na+ channels located in their apical membranes. Whether
this increase is brought up by insertion of new channels in the
membrane from a cytoplasmic pool or by activation of previously
inactive channels remains to be demonstrated.
However, there is a clear discrepancy among the aforementioned
patch-clamp studies of Yue et al. (30) and results obtained across
confluent monolayers of cultured ATII cells. There is clear evidence
that these monolayers contain both amiloride-sensitive and CFTR-type
Cl
channels in their apical membranes. Furthermore,
all published studies agree that terbutaline, forskolin, or 8-CPT-cAMP
activate Cl
currents across cultured ATII cells.
However, the proposed hypothesis that increased Na+
transport is due solely to an increased driving force for
Na+ secondary to activation of Cl
channels cannot explain the sustained increase in
Isc reported in at least two studies and
contradicts the direct measurement of single-channel activation by
terbutaline and PKA.
In trying to explain these apparently contradictory findings, one has
to consider that cultured ATII cells undergo a number of important
phenotypic changes and may be transformed to ATI cells as shown by
their increased immunoreactivity to monoclonal antibodies raised
against ATI cells (6). For example, it is possible that cultured but
not freshly isolated rat ATII cells express functional CFTR. As shown
by Stutts et al. (27), agents that increase cAMP activate
amiloride-sensitive currents across cells transfected with rat
epithelial Na+ channel but not rat epithelial
Na+ channel and CFTR. One way to resolve this controversy
will be to seed ATII cells on clear semipermeable filters and attempt to perform both patch-clamp and Isc measurements in
the same filter.
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ACKNOWLEDGEMENTS |
We acknowledge the editorial assistance of Rebecca Todd.
 |
FOOTNOTES |
This work was supported by National Heart, Lung, and Blood Institute
Grants HL-31197 and HL-51173 and Office of Naval Research Grant
N00014-97-1-0309.
V. G. Nielsen is the recipient of Grant-In-Aid 9810091SE from the
American Heart Association (Southeast Affiliate).
Address for reprint requests and other correspondence: S. Matalon,
Dept. of Anesthesiology, The University of Alabama at Birmingham, THT
940, 619 South 19th St., Birmingham, AL 35249-6810 (E-mail:
Sadis.Matalon{at}ccc.uab.edu).
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