The cGMP-dependent protein kinase stimulates the basolateral
18-pS K channel of the rat CCD
Wen Hui
Wang
Department of Pharmacology, New York Medical College, Valhalla,
New York 10595
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ABSTRACT |
We used the patch-clamp technique to
study the effect of cGMP on the 18-pS K channel in the basolateral
membrane of the rat cortical collecting duct. Addition of 100 µM
8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP)
increased the activity of the 18-pS K channel, defined by
NPo, by 95%. In contrast, applying 8-bromoadenosine 3',5'-cyclic monophosphate (8-Br-cAMP) has
no effect on channel activity. The effect of 8-Br-cGMP was observed only in cell-attached but not in inside-out patches. Application of 1 µM KT-5823, an inhibitor of the cGMP-dependent protein kinase (PKG),
not only reduced the channel activity, but also completely abolished
the stimulatory effect of 8-Br-cGMP, suggesting that the 18-pS K
channel is not a cGMP-gated K channel. Addition of H-89, an agent that
also blocks the PKG, mimicked the effect of KT-5823. To examine the
possibility that the effect of 8-Br-cGMP is the result of inhibiting
cGMP-dependent phosphodiesterase (PDE) and, accordingly, increasing
cAMP or cGMP levels, we explored the effect on the 18-pS K channel of
IBMX, an agent that inhibits the PDE. The addition of 100 µM IBMX had
no significant effect on channel activity in cell-attached patches.
Moreover, in the presence of IBMX, 8-Br-cGMP increased the channel
activity to the same extent as that observed in the absence of IBMX,
suggesting that the effect of cGMP is not mediated by inhibiting the
cGMP-dependent PDE. That the effect of cGMP is mediated by stimulating
PKG was further indicated by experiments in which application of
exogenous PKG restored the channel activity when it decreased after the excision of the patches. In contrast, adding exogenous cAMP-dependent protein kinase catalytic subunit failed to reactivate the
run-down channels. We conclude that cGMP stimulates the 18-pS channel, and the effect of cGMP is mediated by PKG.
nitric oxide; basolateral K conductance; K transport; renal K
channel
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INTRODUCTION |
IN PREVIOUS EXPERIMENTS we have demonstrated that
neuronal nitric oxide synthase (nNOS) is expressed in principal cells
of the rat cortical collecting duct (CCD) (23). Moreover, RT-PCR analysis indicates that soluble guanylate cyclase is present in the rat
CCD (16, 19). The immunocytochemical study further demonstrates that
type II of guanylate cyclase was expressed in the principal cell of the
rat CCD (16), suggesting the possible relationship between nitric oxide
(NO) and the cGMP-dependent signal transduction system. Indeed, we have
previously shown that addition of NO donors increased the intracellular
cGMP levels in the rat CCD (14). The CCD is involved in K secretion and the hormone-regulated Na transport (5, 11). Although the physiological
role of the cGMP-dependent signal transduction pathway in the CCD is
not completely understood, several studies have shown that cGMP may
play an important role in regulating the basolateral K conductance (7,
15). Hirsch et al. have shown that application of cGMP hyperpolarizes
cell membrane potential in the CCD (7). The effect of cGMP on the
basolateral K conductance is most likely mediated by cGMP-dependent
protein kinase (PKG) because PKG stimulates the activity of the 148-pS
and 67-pS K channels in the basolateral membrane (7).
We have recently demonstrated that NO stimulates the low-conductance K
channel, the third type of basolateral K channel in the rat kidney
(15). The stimulatory effect of NO is mediated by a cGMP-dependent
pathway because application of the membrane-permeant cGMP analog mimics
the effect of NO. However, it is not clear whether the effect of cGMP
on the low-conductance K channel is also mediated by a PKG-dependent
mechanism. In the present study, we examine the mechanism by which cGMP
stimulates the low-conductance K channel in the rat CCD.
 |
METHODS |
Preparation of rat CCD.
The experiments were carried out in the isolated CCDs from kidneys of
pathogen-free Sprague-Dawley rats. The animals were obtained from
Taconic (Germantown, NY) and maintained on a high-potassium diet (10%)
for 10 days before use. The weight of the animals used for experiments
was between 100 and 120 g. The method to kill the rats was described
previously (21). After euthanization, the abdomen of the animal was cut
open and the two kidneys were rapidly removed. Several thin slices of
the kidney (<1 mm) were cut and placed on ice-cold Ringer solution
until dissection. The dissection was carried out at room temperature,
and two watch-maker forceps were used to isolate the single CCD. The
tubules were placed onto a 5 mm × 5 mm cover glass
coated with Cell-Tak (Collaborative Research, Bedford, MA) to
immobilize the tubules and transferred to a chamber (1,000 µl)
mounted on an inverted Nikon microscope. The CCDs were superfused with
HEPES-buffered NaCl solution, and the temperature of the chamber was
maintained at 37 ± 1°C by circulating warm water surrounding the
chamber. The CCD was cut open with a sharpened micropipette to expose
the apical membrane. The method to expose the basolateral membrane was
previously described (10). We patched only principal cells that were
recognized by their morphological characteristics described previously
(10).
Patch-clamp technique.
We used an Axon 200A 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 acquired to an
IBM-compatible Pentium computer (Gateway 2000) at a rate of 4 kHz
through a Digidata 1200 interface (Axon Instruments, Burlingame, CA).
Data were analyzed using the pCLAMP software system 6.04 (Axon
Instruments). Channel activity was defined as NPo,
a product of channel number (N) and channel open probability
(Po). The NPo was calculated
from data samples of 30- to 60-s duration in the steady state as
follows
where
ti is the fractional open time spent at
each of the observed current levels. The channel conductance was
determined by measuring the current amplitude at three different voltages.
Experimental solution and statistics.
The pipette solution contained (in mM) 140 KCl, 1.8 MgCl2,
1 EGTA, and 10 HEPES (pH 7.40). The bath solution for cell-attached patches was composed (in mM) of 140 NaCl, 5 KCl, 1.8 CaCl2,
1.8 MgCl2, 5 glucose, and 10 HEPES (pH 7.40), and the
composition of the solution used for excised patches was the same as
that in cell-attached patches except that Ca2+ was 100 nM.
H-89, 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP), KT-5823, and purified PKG were purchased from Biomol (Plymouth Meeting, PA), and IBMX and 8-bromoadenosine
3',5'-cyclic monophosphate (8-Br-cAMP) were obtained from
Sigma (St. Louis, MO). Data are shown as means ± SE, and
the paired Student's t-test was used to determine the
significance of differences between control and experimental periods.
Statistical significance was taken as P < 0.05.
 |
RESULTS |
Figure 1 is a current-voltage
(I-V) curve of the low-conductance K channel in inside-out
patches with symmetrical 140 mM KCl solutions in the pipette and bath
solution, yielding the inward slope conductance of 18 pS. Thus it is
apparent that three types of K channels, 148-pS (cell-attached)/85-pS
(inside-out), 67-pS (cell-attached)/28-pS (inside-out), and 27-pS
(cell-attached)/18-pS (inside-out), are present in the basolateral
membrane of rat CCD (8, 22). We have previously shown that the 18-pS K
channel is activated by cGMP (15). However, it is not know whether PKG mediates the effect of cGMP and stimulates the activity of the 18-pS K
channel. Figure 2A is a
representative channel recording showing the effect of cGMP on the
activity of the 18 pS in a cell-attached patch. Application of 100 µM
8-Br-cGMP increases the channel activity from 0.8 ± 0.1 to
2.2 ± 0.1 (Fig. 2B). We observed that cGMP increased the
channel activity in cell-attached patches by 95 ± 5% in nine experiments. In contrast, cGMP had no significant effect on channel activity in inside-out patches (data not shown). After confirming that
cGMP stimulates the 18-pS K channel, we examined the mechanism by which
cGMP regulates the channel activity. To determine whether the effect of
cGMP is mediated by a PKG-dependent signal transduction pathway, we
examined the effect of H-89, an inhibitor of PKG, on the channel
activity. Figure 3 is a representative
channel recording showing the effect of inhibiting PKG. It is apparent that addition of 1 µM H-89 reduced the activity of the 18-pS K channel by 85 ± 5% (n = 5). The effect of H-89 was
reversible because washout restored the channel activity. In addition
to blocking PKG, H-89 is a more specific inhibitor for cAMP-dependent protein kinase (PKA) than PKG. To exclude the possibility that the
effect of H-89 was the result of inhibiting PKA, we investigated whether stimulating PKA could activate the 18-pS K channel. Figure 4 is a representative channel recording out
of 10 experiments showing the effect of 100 µM 8-Br-cAMP on the 18-pS
K channel in a cell-attached patch. It is apparent that cAMP had no
effect on the channel activity. That the effect of H-89 was induced by inhibiting PKG was further confirmed by experiments using KT-5823, an
agent that is a more specific inhibitor of PKG than H-89. Figure 5 is a recording demonstrating the effect
of KT-5823. Addition of 1 µM KT-5823 reduced the activity of the
18-pS K channel in cell-attached patches by 90 ± 5% (n = 5).
Moreover, the presence of KT-5823 completely abolished the effect of
cGMP (Fig. 5). Figure 6 summarizes the
results showing the effect of 8-Br-cGMP in the presence and in the
absence of the PKG inhibitor. It is clear that inhibition of PKG
abolished the effect of cGMP. In addition to stimulation of PKG, cGMP
has been shown to inhibit or stimulate the cGMP-dependent
phosphodiesterase (PDE) and, accordingly, alter the intracellular cAMP
or cGMP levels. If the effect of cGMP was the result of regulating PDE
activity, the cGMP-inhibited PDE isoform should be involved because
this would increase cAMP/cGMP concentration (12). To determine whether
the effect of cGMP was mediated by inhibiting PDE, we examined the
effect of IBMX, an inhibitor of PDE. Figure
7 is a channel recording illustrating the
effect of IBMX. Application of 100 µM IBMX had no significant effect
on the channel activity (n = 6). Moreover, in the presence of
IBMX, adding 100 µM 8-Br-cGMP significantly increased channel activity. Figure 6 summarizes the effects of IBMX and cGMP+IBMX. It is
clearly demonstrated that inhibition of PDE failed to mimic the effect
of cGMP and that application of 8-Br-cGMP increased the channel
activity by 125 ± 11% (n = 6) in the presence of IBMX. That
the effect of 8-Br-cGMP is the result of stimulating PKG is further
supported by experiments in which application of exogenous PKG restored
the activity of the 18-pS channel when it decreased upon excision.
Figure 8 is a representative recording from
three such experiments showing the effect of PKG. After forming an
inside-out patch, the channel activity decreased rapidly. The addition
of 1 nM exogenous PKG in the presence of cGMP restored the channel activity to the original level. In contrast, adding exogenous PKA
catalytic subunit failed to reactivate the 18-pS channel (data not
shown). This indicates that PKG plays an important role in regulating
the 18-pS K channel.

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Fig. 1.
Current-voltage (I-V) curve produced in inside-out patches with
symmetrical 140 mM KCl solution in bath and in pipette.
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Fig. 2.
A: channel recording showing effect of 100 µM
8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP).
Experiment was carried out in a cell-attached patch, and pipette
holding potential was 0 mV. Top, time course of experiment; 2 parts of trace indicated by numbers are extended to demonstrate detail
of channel activity. C, channel close level. B: all points of
histogram show NPo obtained under control
conditions and in presence of 100 µM 8-Br-cGMP. Arrows indicate
channel close level (C). The y axis represents events
account.
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Fig. 3.
A representative channel recording showing effect of 1 µM H-89.
Experiment was performed in a cell-attached patch, and holding
potential was 0 mV. Four parts of trace indicated by numbers are
extended at fast time resolution.
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Fig. 4.
A channel recording showing effect of 100 µM 8-bromoadenosine
3',5'-cyclic monophosphate (8-Br-cAMP) on 18-pS K channel
in a cell-attached patch. Top, time course of experiments; 2 parts of trace indicated by numbers 1 and 2 are extended at a fast time
resolution. C, channel close level.
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Fig. 5.
Effect of KT-5823 on channel activity in a cell-attached patch.
Top, time course of experiments; 4 parts of trace are extended
at fast time resolution. Holding potential is 0 mV.
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Fig. 6.
Effect of 100 µM 8-Br-cGMP (cGMP) (n = 9), cGMP+KT-5823 (1 µM) (n = 5), 100 µM IBMX, and IBMX+cGMP (n = 6) on
channel activity. * Indicates that difference between control and
experimental group is significant (P < 0.05).
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Fig. 7.
A channel recording showing effect of 100 µM IBMX and 100 µM
8-Br-cGMP. Experiment was performed in a cell-attached patch, and
holding potential was 0 mV. Top, time course of experiment; 3 parts of trace indicated by numbers are demonstrated at an extended
scale.
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Fig. 8.
Effect of 1 nM exogenous cGMP-dependent protein kinase (PKG) on channel
activity in an inside-out patch. Patch was excised to a bath solution
containing 100 µM ATP and 100 µM cGMP. After channel run-down, 1 nM
PKG was added to bath solution. Membrane potential was 30 mV.
Top, time course; 3 parts of trace are shown at fast time
resolutions.
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DISCUSSION |
The basolateral K channels play an important role in determination of
cell membrane potential. Because both Na reabsorption and K secretion
are electrogenic processes (5, 11), changes in cell membrane potential
should affect the Na and K transport in the CCD. Moreover, the
basolateral K channels are involved in K recycling in the basolateral
membrane. In the present studies, we have demonstrated that PKG plays
an important role in regulating the basolateral 18-pS K channel. In
contrast, PKG has no effect on the apical K channel activity
(unpublished observations). Thus it is possible that the basolateral
and apical K conductance are differently regulated to maintain the
normal function of the CCD (20). Although all three types of K channels
are activated by PKG, the regulatory mechanisms may not be the same
among three K channels. For instance, NO has been shown to directly
activate the 148-pS and 67-pS K channel in inside-out patches (6),
whereas NO has no effect on the 18-pS K channel in excised patches
(15). Moreover, it was demonstrated that the 148-pS K channels are
abundant in the CCD from rats on a low-sodium diet, whereas the 18-pS K channels are the most abundant among three basolateral K channels in
the CCD from rats on a high-potassium diet (14). Therefore, it is
possible that a variety of the transport function in the CCD principal
cells is achieved by a different response of each type of basolateral K
channels to a given stimulation.
It was previously shown that the basolateral K conductance was closely
correlated with the activity of the Na-K-ATPase of the renal collecting
duct (9, 10). We have recently observed that inhibiting apical Na
transport, a maneuver that reduces the turnover rate of the
Na-K-ATPase, decreases the activity of the 18-pS K channel in the
basolateral membrane of the CCD (13). Furthermore, it has been
suggested that NO links the apical Na transport to the activity of the
basolateral K channels because the effect of inhibiting Na transport is
abolished by either adding exogenous NO donors or blocking NOS (13).
The effect of NO is mediated by a cGMP-dependent pathway because cGMP
mimics the action of NO.
There are three possible mechanisms by which cGMP stimulates the
channel activity. First, the effect of cGMP is the result of activating
PKG (4, 12), which increases the channel activity by PKG-induced
phosphorylation of the 18-pS K channel or the associate proteins. PKG
has been shown to stimulate the Ca-activated K channel in the vascular
smooth muscle cells (1). Second, the 18-pS K channel is a cGMP-gated K
channel, and increasing cGMP concentration stimulates the activity of
the 18-pS K channel. Indeed, the cGMP-gated K channels have been found
in the rat kidney (3, 24). Finally, the effect of cGMP is mediated by
raising intracellular cAMP or cGMP levels through inhibiting
cGMP-dependent PDE (2).
Two lines of evidence indicate that the 18-pS channel is not a
cGMP-gated K channel: 1) adding cGMP to the bath-facing
intracellular surface of inside-out patches has no effect on channel
activity, and 2) the stimulatory effect of cGMP is absent in
the presence of PKG inhibitors. It is also unlikely that the effect of
cGMP is mediated by inhibiting PDE because application of IBMX fails to
mimic the effect of cGMP. Although IBMX is not a specific inhibitor for
type III PDE, which is blocked by cGMP (2), IBMX should inhibit all
isoforms of PDE including type III PDE. Thus should the effect of cGMP
be the result of blocking type III PDE, application of IBMX would
stimulate the channel activity to the same extent as that observed with
adding 8-Br-cGMP. In addition, the effect of cGMP should be attenuated
in the presence of IBMX if the effect of cGMP was mediated by
activating type III PDE. However, our results have shown that the
effect of cGMP is slightly enhanced in the presence of IBMX, presumably
due to blocking hydrolysis of cGMP. This notion was further supported
by experiments in which adding exogenous PKA had no effect on the
activity of the 18-pS K channel, and applying the
membrane-permeant cAMP analog failed to stimulate the channel activity,
suggesting that the 18-pS K channel may not be regulated by a
cAMP-dependent pathway.
Three lines of evidence support the notion that the effect of cGMP is
mediated by a PKG-dependent mechanism: 1) inhibition of PKG
reduced channel activity, 2) application of PKG inhibitors abolished the effect of cGMP, and 3) adding exogenous PKG
restored the run-down channel activity.
Although cGMP stimulates the 18-pS K channel, it is not known whether
cGMP could affect the net Na transport in the CCD. Application of NO
donors or cGMP-activating peptides has been shown either to inhibit or
to have no effect on the Na transport in the CCD (6, 17, 18). One
possible reason causing the discrepancy is that different
concentrations of NO donors were used in experiments. We have observed
that high concentrations of NO inhibited the 18-pS K channel, whereas
low concentrations of NO stimulated the 18-pS K channel (13, 14).
Moreover, because several transporters are involved in regulating the
Na reabsorption and several mechanisms are involved in modulating one
given transporter, it is conceivable the net effect of NO and
cGMP-activating peptides on the Na transport would also depend on
factors other than cGMP.
PKG may play an important role in linking the apical Na transport to
the basolateral K conductance. Stimulating Na transport tends to
increase intracellular Na concentration and, accordingly, intracellular
Ca that activates the nNOS in the principal cell and enhances the
formation of NO. Subsequently, NO stimulates the soluble guanylate
cyclase and raises the intracellular cGMP level, which in turn
increases the basolateral K conductance by the PKG-dependent pathway.
We conclude that cGMP stimulates the basolateral 18-pS K channel, and
the effect of cGMP is mediated by the PKG-dependent pathway.
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ACKNOWLEDGEMENTS |
The author thanks M. Steinberg for editorial assistance.
 |
FOOTNOTES |
This work was supported by National Institute of Diabetes and Digestive
and Kidney Diseases Grant RO1DK-47402 and National Heart, Lung, and
Blood Institute Grant P01HL-34300 (W. H. Wang).
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, BSB Rm. 537, Valhalla,
NY 10595 (E-mail: wenhui_wang{at}nymc.edu).
Received 9 November 1999; accepted in final form 30 December 1999.
 |
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