Vasopressin and PGE2 regulate activity of apical 70 pS K+ channel in thick ascending limb of rat
kidney
Hua Jun
Liu,
Yuan
Wei,
Nicholas R.
Fererri,
Alberto
Nasjletti, and
Wen Hui
Wang
Department of Pharmacology, New York Medical College, Valhalla,
New York 10595
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ABSTRACT |
Vasopressin and prostaglandin
E2 (PGE2) are involved in regulating NaCl
reabsorption in the thick ascending limb (TAL) of the rat kidney. In
the present study, we used the patch-clamp technique to study the
effects of vasopressin and PGE2 on the apical 70 pS
K+ channel in the rat TAL. Addition of vasopressin
increased the channel activity, defined as
NPo, from 1.11 to 1.52 (200 pM) and 1.80 (500 pM),
respectively. The effect of vasopressin can be mimicked by either
forskolin (1-5 µM) or 8-bromo-cAMP/dibutyryl-cAMP (8-Br-cAMP/DBcAMP) (200-500 µM). Moreover, the effects of cAMP and vasopressin were not additive and application of 10 µM H-89 abolished the effect of vasopressin. This suggests that the effect of
vasopressin is mediated by a cAMP-dependent pathway. Applying 10 nM
PGE2 alone had no significant effect on the channel
activity. However, PGE2 (10 nM) abolished the
stimulatory effect of vasopressin. The PGE2-induced
inhibition of the vasopressin effect was the result of decreasing cAMP
production because addition of 200 µM 8-Br-cAMP/DBcAMP
reversed the PGE2-induced inhibition. In addition to
antagonizing the vasopressin effect, high concentrations of PGE2 reduced channel activity in the absence of vasopressin
by 33% (500 nM) and 51% (1 µM), respectively. The inhibitory effect of high concentrations of PGE2 was not the result of
decreasing cAMP production because adding the membrane-permeant cAMP
analog failed to restore the channel activity. In contrast, inhibiting protein kinase C (PKC) with calphostin C (100 nM) abolished the effect
of 1 µM PGE2. We conclude that PGE2 inhibits
apical K+ channels by two mechanisms: 1) low
concentrations of PGE2 attenuate the vasopressin-induced
stimulation mainly by reducing cAMP generation, and 2) high
concentrations of PGE2 inhibit the channel activity by a
PKC-dependent pathway.
cyclooxygenase; cAMP; protein kinase C; patch-clamp technique; NaCl
transport
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INTRODUCTION |
THE THICK ASCENDING LIMB (TAL) is responsible for
reabsorption of 20-25% of the filtrated Na+ load and
plays a key role in the urinary concentrating mechanism (16, 17).
Na+ enters the cell through the luminal
Na+-K+-Cl
cotransporter
energized by a favorable electrochemical gradient of Na+
and is then pumped out of the cell through the basolateral
Na+-K+-ATPase. K+ recycling is
essential for maintaining the normal function of the
Na+-K+-Cl
cotransporter (16,
19). First, K+ recycling hyperpolarizes the cell membrane
and accordingly provides the driving force for Cl
leaving the cell. Second, K+ recycling participates in
generating the lumen-positive potential, which is the driving force for
transepithelial Na+, Ca2+, and Mg2+
transport. Third, K+ recycling is important for providing
an adequate supply of K+ to the
Na+-K+-Cl
cotransporter in
the cortical TAL where the K+ concentration is at least one
order of magnitude lower than that of Na+ and
Cl
.
Three types of K+ channels, 70 pS, 30 pS, and
Ca2+-activated maxi K+ (>100 pS), have been
expressed in the apical membrane of the TAL (5, 32, 33). However, it is
generally believed that the 70 pS and the 30 pS K+ channels
are responsible for K+ recycling across the apical membrane
(34). This conclusion is based on observations that both channels have
a higher channel open probability as well as a larger number of
channels per cell than that of the maxi K+ channel in the
TAL (5, 33). The 70 pS K+ channel is sensitive to MgATP,
inhibited by acidic pH and protein kinase C (PKC), and stimulated by
cAMP-dependent protein kinase (PKA) (5, 35). Furthermore, patch-clamp
experiments demonstrated that the 70 pS K+ channel and the
30 pS K+ channel contribute to the apical K+
conductance by ~80% and 20%, respectively (35). Thus the 70 pS
K+ channel should play a key role in K+ recycling.
Prostaglandin E2 (PGE2) plays an important role
in regulating Cl
reabsorption in the TAL (13, 21,
27). The effect of PGE2 is mediated by inhibition of
vasopressin-induced increase in cAMP level. Because K+
recycling plays an important role in maintaining the function of the
Na+-K+-Cl
cotransporter, it
is possible that the effect of PGE2 on NaCl transport in
the TAL involves the regulation of apical K+
channels. Therefore, the present study is designed to
investigate the effect of interaction between PGE2 and
vasopressin on channel activity.
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METHODS |
Preparation of the TAL.
The pathogen-free Sprague-Dawley rats (100-120 g) used in
experiments were purchased from Taconic (Germantown, NY). Animals were
killed by cervical dislocation after anesthesia with Metofane. The kidneys were removed immediately and thin coronal sections were cut
with a razor blade. We used only medullary TALs in the study. The
dissection buffer solution contained (in mM) 140 NaCl, 5 KCl, 1.5 MgCl2, 1.8 CaCl2, 5 glucose, and 10 HEPES (pH
7.4 with NaOH) at 22°C. The isolated tubule was transferred onto a
5 × 5 mm cover glass coated with Cell-Tak (Collaborative
Research, Bedford, MA) to immobilize the tubule. The cover glass was
placed in a chamber mounted on an inverted microscope (Nikon) and the tubules were superfused with HEPES-buffered NaCl solution, composed of
(in mM) 140 NaCl, 5 KCl, 1.8 CaCl2, 1.8 MgCl2,
and 10 HEPES (pH 7.4). The TAL was cut open with a sharpened
micropipette to gain access to the apical membrane. The temperature of
the chamber (1,000 µl) was maintained at 37 ± 1°C by
circulating warm water around the chamber.
Patch-clamp technique.
We used an Axon200A patch-clamp amplifier to record channel current.
The current was low-pass filtered at 1 kHz using an eight-pole Bessel
filter (902LPF; Frequency Devices, Haverhill, MA) and was digitized at
a sampling rate of 44 kHz using a digital data recorder (model VR-10B;
Instrutech Great Neck, NY) and stored on videotape (Sony SL-2700). For
analysis, data stored on the tape was collected to an IBM-compatible
Pentium computer (Gateway 2000) at a rate of 4 kHz and analyzed using
the pCLAMP software system 6.04 (Axon Instruments, Burlingame, CA).
Opening and closing transitions were detected using 50% of the
single-channel amplitude as the threshold. Channel activity was defined
as NPo. The NPo was calculated from data samples of 30-60 s duration that were always at the end
of each experimental maneuver and in the steady state. We used the
following equation to obtain NPo
|
(1)
|
where
ti is the fractional open time spent at
each of the observed current levels. Because two types of
K+ channels are present in the apical membrane of TAL, two
types of K+ channels sometimes can be detected in the same
patches. To avoid this complexity, we have selected those patches with
only a single population of K+ channel to calculate
NPo. If the low-conductance K+ channel
appeared during the course of experiments, we used a ruler to calculate
NPo manually.
Chemicals and experimental solution.
The pipette solution contained (in mM) 140 KCl, 1.8 MgCl2,
and 10 HEPES (pH=7.4). Forskolin, 8-Br-cAMP, and DBcAMP were purchased from Sigma (St. Louis, MO) and forskolin was dissolved in DMSO. PGE2 and calphostin C were obtained from Biomol (Plymouth
Meeting, PA) and dissolved in ethanol. The final concentration of
either DMSO or ethanol in experiments was less than 0.1% and had no
effect on channel activity. The chemicals were added directly to the bath to reach the final concentration.
Statistics.
Data are shown as mean ± SE. We used paired Student's
t-tests to determine the significance of difference between the
control and experimental periods. Statistical significance was taken as P < 0.05.
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RESULTS |
We have previously observed that application of vasopressin stimulated
the 30 pS K+ channel in the apical membrane of the TAL
(33). We extended our study to examine the effect of vasopressin on the
activity of the 70 pS K+ channel. Figure
1A is a
representative channel recording showing the effect of vasopressin on
the 70 pS K+ channel in a cell-attached patch. It is
apparent that vasopressin significantly stimulates the activity of the
70 pS K+ channel. Application of 200 and 500 pM vasopressin
increased the NPo from 1.11 ± 0.1 to 1.52 ± 0.16 and 1.80 ± 0.2 (n = 7), respectively (Fig. 1B).
The effect of vasopressin was reversible because the channel activity
returned to the control value after removal of vasopressin. To
determine whether the effect of vasopressin is mediated by a
cAMP-dependent pathway, we investigated the effect of 1-5 µM
forskolin, an agent that stimulates the adenylate cyclase, on channel
activity. Figure 2A is a
representative recording demonstrating the effect of forskolin on the
70 pS K+ channel in a cell-attached patch. In five
experiments, addition of 1-5 µM forskolin increased the
NPo from 1.16 ± 0.1 to 1.85 ± 0.2, and the
effect was reversible as the channel activity returned to the control
value after removal of forskolin. That the effect of vasopressin was
mediated by a cAMP-dependent pathway is further suggested by
observations that application of the membrane-permeant cAMP analogs
stimulates the channel activity. Figure 2B is a typical recording illustrating the effect of 8-Br-cAMP/DBcAMP on channel activity in a cell-attached patch. Addition of 200-500 µM
8-Br-cAMP/DBcAMP increased NPo from 0.95 ± 0.1 to
1.4 ± 0.12 (n = 4). Figure 2C summarizes the results
regarding the effect of vasopressin, 8-Br-cAMP/DBcAMP, and forskolin.
Vasopressin (500 pM) significantly increased channel activity by 62 ± 7% (n = 7). Similarly, addition of 500 µM
8-Br-cAMP/DBcAMP or 1-5 µM forskolin significantly raised
channel activity by 47 ± 5% (n = 4) and 59 ± 5%
(n = 5), respectively. Moreover, the effects of vasopressin and
cAMP were not additive because addition of vasopressin (500 pM) + DBcAMP increased channel activity by 63 ± 7% (n = 4), a
value that is not significantly different from that observed with
vasopressin alone. This indicates that the effect of vasopressin is the
result of stimulating cAMP generation. To determine whether the effect
of vasopressin is the result of inhibition of PKA, we examined the
effect of vasopressin in the presence of H-89, an inhibitor of PKA
(Fig. 3). Addition of H-89 (10 µM) had no
significant effect on channel activity (control NPo = 0.95 ± 0.08, H-89 = 0.85 ± 0.08). This suggests that PKA is not
required in maintaining the activity of the opened channels. However,
inhibition of PKA completely abolished the effect of vasopressin
because it failed to increase NPo (0.82 ± 0.09)
in the presence of a PKA inhibitor (n = 3). This
indicates that the effect of vasopressin is mediated by PKA and is most
likely the result of stimulation of a V2 cAMP-coupled
receptor.

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Fig. 1.
A: a channel recording shows effect of vasopressin (AVP) on
activity of 70 pS K+ channel in apical membrane of mTAL.
Experiment was performed in a cell-attached patch and holding potential
was 0 mV. C, channel closed level. B: effect of AVP on activity
of apical 70 pS K+ channel. * Data significantly
different from control value; NPo, channel
activity.
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Fig. 2.
A: channel recording showing effect of 1 µM forskolin.
Experiment was carried out in a cell-attached patch and holding
potential was 0 mV. B: recording demonstrates effect of 0.5 mM
DBcAMP on channel activity. Experiment was performed in a cell-attached
patch and holding potential was 30 mV. C: effects of 500 pM AVP, 500 µM DBcAMP/8-Br-cAMP (cAMP), 1-5 µM forskolin, and
cAMP + AVP on channel activity in cell-attached patches. Data are
significantly different from control value.
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Fig. 3.
A: channel recording showing effect of AVP in presence of 10 µM H-89. Experiment was carried out in a cell-attached patch and
holding potential was 0 mV. B: effect of 10 µM H-89
and AVP (500 pM) + 10 µM H-89 on channel activity.
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In addition to a V2 receptor, PGE2 type III
receptor, EP3, is present in the TAL and stimulating the
EP3 receptor has been shown to reduce cAMP production (2,
25). Thus we explored the interaction between vasopressin
and the effect of PGE2 to determine whether
PGE2 can abolish the effect of vasopressin. Figure 4A is a recording showing
the effect of PGE2 on the vasopressin-induced increase in
channel activity. It is clear that 10 nM PGE2 abolished the
vasopressin-induced increase in channel activity. The inhibitory effect
of PGE2 resulted from blocking vasopressin-induced increase in cAMP concentration because addition of cAMP analogs reversed the
effect of PGE2. Figure 4B summarizes the results
from five experiments that examined the interaction between vasopressin and PGE2. Adding 200 pM vasopressin increased
NPo from the control value (0.80 ± 0.07) to 1.14 ± 0.10. However, in the presence of vasopressin,
application of 10 nM PGE2 abolished the effect of vasopressin and the NPo decreased to 0.75 ± 0.07, a value that is not significantly different from the control. Moreover,
addition of 200 µM DBcAMP raised the NPo from
0.75 ± 0.07 to 1.07 ± 0.10 in the presence of PGE2.

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Fig. 4.
A: channel recording shows that prostaglandin E2
(PGE2) abolished stimulatory effect of 200 pM AVP.
Experiment was performed in a cell-attached patch and holding potential
was 0 mV. Arrows indicate where PGE2 and DBcAMP (200 µM)
were added. B: effects of AVP (200 µM),
PGE2 (10 nM) + AVP, and 200 µM DBcAMP/8-Br-cAMP + PGE2 + AVP on channel activity. *Data significantly
different from control.
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That the effect of 10 nM PGE2 was the result of inhibiting
vasopressin-induced increase in cAMP level was further confirmed by
experiments where in the absence vasopressin, 10 nM PGE2
had no significant effect on the channel activity (Fig.
5A). However, further increase of
PGE2 concentration to 1 µM significantly decreased channel activity by 51%, and NPo decreased from
1.39 to 0.67. The inhibition induced by high concentrations of
PGE2 was not the result of decreasing cAMP concentration
because adding 500 µM DBcAMP failed to restore the channel activity
and NPo slightly increased from 0.67 to 0.8 (Fig.
5B).

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Fig. 5.
A: channel recording shows effect of 10 nM PGE2, 1 µM PGE2, and 500 µM DBcAMP + 1 µM PGE2.
Experiment was carried out in a cell-attached patch and holding
potential was 30 mV. B: dose-response curve of
PGE2 on channel activity. Experiments were performed in
absence of AVP. *Significantly different from control (100%).
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Figure 5B is a dose-response curve of PGE2 effect
in the absence of vasopressin, showing that addition of 500 nM, 1 µM,
and 10 µM PGE2 reduced channel activity by 33 ± 3%
(n = 4), 51 ± 5% (n = 11), and 55 ± 5% (n = 4), respectively. Because PGE2 has been shown to
stimulate PKC, we investigated the role of PKC in mediating the effect
of high concentrations of PGE2. Figure
6 is a representative recording from seven
such experiments showing the effect of calphostin C, an agent that
inhibits PKC, on 1 µM PGE2-induced decrease in channel
activity. As demonstrated in Fig. 6A, 1 µM PGE2
reduced channel activity by 51 ± 5%, and adding 500 µM DBcAMP
increased channel activity slightly to 60 ± 7% of the control value.
In contrast, inhibiting PKC completely restored channel activity to the
control value (Fig. 6B). The notion that the effect of high
concentrations of PGE2 is mediated by a PKC-dependent pathway was also indicated by experiments where in the presence of
calphostin C, the inhibitory effect of 1 µM PGE2 was
completely abolished (Figs. 6 and 7). Figure
7 is a representative recording from five
experiments showing that addition of calphostin C had no significant
effect on channel activity (105 ± 5% of the control). However, in
the presence of a PKC inhibitor, addition of 1 µM PGE2
had no significant effect on the K+ channel because channel
activity was still 102 ± 5% of the control value.

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Fig. 6.
A: channel recording demonstrates effect of 1 µM
PGE2 on channel activity in presence of 500 µM DBcAMP and
100 nM calphostin C. Experiment was performed in a cell-attached patch
and holding potential was 0 mV. B: effects of 10 nM
PGE2, 1 µM PGE2, 500 µM DBcAMP + 1 µM
PGE2, and 100 nM calphostin C + 1 µM PGE2 on
channel activity. Channel activity was normalized by comparing to
corresponding control NPo. * Data significantly
different from control value.
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Fig. 7.
Channel recording showing effect of 1 µM PGE2 in presence
of 100 nM calphostin C. Experiment was performed in a cell-attached
patch and holding potential was 0 mV. Time course of experiments
(A) and 3 parts of trace (B) are demonstrated at a fast
time resolution.
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DISCUSSION |
The main finding of the present study is that low concentrations of
PGE2 abolish the stimulatory effect of vasopressin on the
apical 70 pS K+ channel, whereas high concentrations of
PGE2 inhibit the channel activity via a PKC-dependent
pathway. Because the 70 pS K+ channel is the most abundant
K+ channel in the apical membrane of the rat TAL, the
effect of PGE2 on the 70 pS K+ channel should
inhibit the K+ recycling across the apical membrane.
That K+ recycling is essential for maintaining normal
function of the Na+-K+-Cl
cotransporter is convincingly demonstrated by a genetic study showing
that a defective gene product encoding renal outer medulla K+ (ROMK) channels led to an abnormal salt transport in
human kidney, Bartter's syndrome (30). Although it is well established
that the ROMK channel family is a key component of the 30 pS
K+ channel (26, 34), the relationship between the 70 pS
K+ channel and ROMK is not clear. Because the 70 pS
K+ channel could contribute as much as 80% of
K+ conductance to the apical membrane of the rat TAL,
K+ recycling is unlikely to be severely compromised by only
a 20% decrease in the apical K+ conductance. Thus it is
possible that ROMK is also involved in forming the 70 pS K+
channel. If the 70 pS K+ channel is not expressed in the
apical membrane of the TAL of human kidney, the mechanism by which
PGE2 inhibits the 70 pS K+ channel is still
physiologically relevant for understanding the role of PGE2
in regulating K+ recycling across the apical membrane of
the TAL because ROMK channels are also regulated by PKA and PKC (24,
34, 37).
In the present study, we have demonstrated that vasopressin activates
the apical K+ channels. Vasopressin has been shown to
stimulate NaCl transport in the TAL of mouse kidney (17). The effect of
vasopressin is mediated by a cAMP-dependent pathway because cAMP mimics
the effect of vasopressin. Moreover, the effect is the result of
stimulating PKA-induced phosphorylation of basolateral
Cl
channels, apical
Na+-K+-Cl
cotransporters,
and K+ channels (16, 18, 20). In previous studies, we
demonstrated that vasopressin stimulated the 30 pS K+
channel in the rat TAL and cortical collecting duct (11,
33). Now, we have shown that vasopressin can also increase the activity of the 70 pS K+ channel. Three lines of evidence support
the notion that the effect of vasopressin is mediated by a
cAMP-dependent pathway: 1) addition of either forskolin or
membrane-permeant cAMP analogs mimics the effect of vasopressin,
2) the effects of vasopressin and cAMP are not additive, and
3) inhibition of PKA abolishes the effect of vasopressin. The
notion that PKA mediates the stimulatory effect of vasopressin is also
confirmed by studies on renal medullary vesicles (28).
In addition to vasopressin, PGE2 has been shown to play an
important role in regulating NaCl transport in the TAL (12, 13, 21,
31). Several studies have demonstrated that PGE2 blocks the
stimulatory effect of vasopressin on NaCl transport in the TAL (12, 13,
21). Moreover, the effect of PGE2 was induced by inhibiting
vasopressin-dependent increase in cAMP generation (7, 13). Although we
cannot completely exclude the role of PKC, two lines of evidence
indicate that the effect of low concentrations (<100 nM) of
PGE2 on channel activity is mainly produced by decreasing vasopressin-induced increase in cAMP generation. First,
PGE2 had no significant effect on channel activity in the
absence of vasopressin. Second, applying exogenous cAMP analogs
abolishes the inhibitory effect of PGE2. In addition to
antagonizing the effect of vasopressin, we demonstrated that high
concentrations of PGE2 (>500 nM) can inhibit channel
activity via a cAMP-independent mechanism. Because blocking PKC
abolishes the inhibition induced by high concentrations of
PGE2, the effect is most likely mediated by a PKC-dependent pathway.
Four types of PGE2 receptors, EP1,
EP2, EP3, and EP4, have been
identified in kidneys (1, 4, 7, 8, 36). Immunocytochemical studies have
revealed that the main type of PGE2 receptor expressed in
the mTAL is the EP3 receptor, which is coupled to
Gi protein. Thus the effect of low concentrations of
PGE2 should be the result of stimulating the
Gi-coupled EP3 receptor. However, the
EP1 receptor, which is linked to phospholipase C, is not
identified in the mTAL (8, 9). There are two possibilities to explain
how high concentrations of PGE2 can stimulate the
PKC-dependent pathway: 1) some EP3 receptors with
low affinity could be alternatively coupled to phopholipase C, and
2) a low level of EP1 receptors, which is not
detected with the current methodology, may be expressed in the mTAL.
The first possibility is supported by findings showing that
EP3 receptors have several alternatively spliced variants and these variants can couple to different signaling mechanisms including phosphatidylinositol biphosphate hydrolysis (2, 25). Because
the EP3 receptor, which does not couple to Gi
protein, has a low affinity to PGE2, low concentrations of
PGE2 cannot activate these variants. Our finding that
PGE2 could activate the PKC-dependent pathway is also
consistent with Good's observation that PGE2 causes
selective activation of the PKC-
isoform (3, 15). Moreover, the fact
that high concentrations of PGE2 inhibit the apical
K+ channels by a PKC-dependent mechanism may also be
important to understand the beneficial effect of inhibiting
prostaglandin synthesis in treatment of Bartter's syndrome. One of the
characteristics of Bartter's syndrome is an increase in plasma
PGE2 level (29). Inhibition of cyclooxygenase (COX)
improves the manifestation of the disease (27). Because NaCl transport
in the TAL is severely compromised in patients with Bartter's
syndrome, high concentrations of PGE2 further diminish the
remaining function of the TAL. Therefore, inhibition of
PGE2 production should improve the transport function of
the TAL cells.
PGE2 is the product of COX-dependent metabolism of
arachidonic acid (AA). There are at least two AA
metabolic pathways in the mTAL: COX and cytochrome P-450
monooxygenase-dependent metabolisms (6, 23). A major metabolite of the
cytochrome P-450-dependent pathway in the mTAL (10),
20-hydroxyeicosatetraenoic acid, has been shown to regulate the
activity of the 70 pS K+ channel (35) and
Na+-K+-Cl
cotransporter
(14). Thus the cytochrome P-450-dependent pathway should play a
key role in the regulation of NaCl transport in the TAL (34). On the
other hand, hypercalcemia has been shown to increase PGE2
production. This increase in PGE2 may be partially responsible for diminished transport function in the loop of Henle during hypercalcemia (22). However, it is not known whether the
COX-dependent pathway interacts with P-450-dependent metabolism of AA. We need further experiments to explore the role of interaction between the two AA metabolic pathways in the regulation of the transport function of the TAL.
Figure 8 is a model of the TAL cell
illustrating the mechanism by which PGE2 regulates the
apical K+ channels and possibly the NaCl transport in the
mTAL. Low concentrations of PGE2 antagonize the stimulatory
effect of vasopressin on the apical K+ conductance, whereas
high concentrations inhibit the apical K+ channel by PKC
stimulation.

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Fig. 8.
Model of thick ascending limb (TAL) cell illustrating mechanism
by which PGE2 regulates apical K+ channels.
Arrows and double bars represent stimulation and inhibition,
respectively; PKA, cAMP-dependent protein kinase; PKC, protein kinase
C; AC, adenylyl cyclase.
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ACKNOWLEDGEMENTS |
We thank M. Steinberg for editorial assistance.
 |
FOOTNOTES |
This work was supported by National Heart, Lung, and Blood
Institute Grant PO1HL-34300 and National
Institute of Diabetes and Digestive and Kidney Diseases Grant DK-47402.
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: W. H. Wang,
Dept. of Pharmacology, New York Medical College, Grasslands
Reservation, Valhalla, NY 10595 (E-mail:
wenhui_wang{at}nymc.edu).
Received 12 August 1999; accepted in final form 17 November 1999.
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