K+channels play an important role in regulating the mem-
brane potential of smooth muscles and their excitability. Gen-
erally, outward K+current oppose membrane excitability via
K+channels. In a variety of cells including gastrointestinal
(GI) tract, several types of K+channels which are activated
by diverse intracellular factors, such as Ca2+and ATP have
been reported (1-7). The best known among them is Ca2+-acti-
vated K+channel (K(Ca) channel) whose gating is regulated
by concentration of intracellular free Ca2+([Ca2+]i) (3-6). K(Ca)
channel participates principally in the rapid repolarization
of Ca2+-dependent action potentials (8). Voltage-dependent
and Ca2+-independent K+channels (K(V) channel) and ATP-
sensitive K+channel (KATP channel) in smooth muscles are
also known well (1, 7, 9). In GI tract, basal activation of KATP
channel has been shown to contribute to control of resting
membrane potential (RMP) (9). Recently, pH-sensitive two-
pore K+channels of the TASK family have also been report-
ed in murine GI tract (10). Therefore, it seems that more types
of K+channels still exist in GI smooth muscles. In fact, there
is another class of K+channel not reported in GI smooth mus-
cle cells. This is known as K(Na) channel, which is activated
by intracellular Na+([Na+]i). It was reported in guinea pig
ventricular myocytes (11).
Since its isolation from cardiac myocytes, the gating of K(Na)
channel has been known to be activated by intracellular Na+,
but not by Ca2+and ATP or other nucleotides (12). Depend-
ing on cell types and recording conditions, reported unitary
conductance of K(Na) channel ranges from 105 to 200 pS and
half-maximal activation by Na+occurs between 7 and 80 mM
(13). K(Na) channel of the heart was suggested to be activated
under pathophysiological conditions such as during failure
of the Na+-K+pump (11). Also K(Na) channel has been pro-
posed to be activated by a single action potential and could
be involved in setting RMP in neuronal cell (14-16). To date,
however, the existence of K(Na) channel in smooth muscles has
not been reported yet. In GI tract, spontaneous contraction
and slow wave are dependent on extracellular Na+concentra-
tion: In the duodenum and ileum, low Na+decreased ampli-
Young Chul Kim, Jae Hoon Sim*,
Tong Mook Kang
Seung Ryul Kim
Wen-Xie Xu¶, Sang Jin Lee,
Ki Whan Kim*
�, Hikaru Suzuki
�, Seong-Chun Kwon‖,
Departments of Physiology, Biochemistry
National University, College of Medicine, Cheongju;
Department of Physiology & Biophysics*, Seoul
National University, College of Medicine, Seoul;
Department of Physiology
School of Medicine, Suwon, Korea; Department of
Nagoya, Japan; Department of Physiology‖, College
of Medicine, Kwandong University, Gangneung, Korea;
Department of Physiology¶, Medical School, Shanghai
Jiaotong University, Shanghai, China
�, Sungkyunkwan University,
�, Nagoya City University Medical School,
Address for correspondence
Young Chul Kim
Department of Physiology, Chungbuk National
University College of Medicine, 12 Gaeshin-dong,
Heungduk-gu, Cheongju 361-763, Korea
Tel : +82.43-261-2859, Fax : +82.43-261-2859
E-mail : firstname.lastname@example.org
*This work was supported by Korea Research Foun-
dation Grant (KRF-2003-015-E00020).
J Korean Med Sci 2007; 22: 57-62
Copyright � The Korean Academy
of Medical Sciences
Sodium-activated Potassium Current in Guinea pig Gastric Myocytes
Received : 2 June 2006
Accepted : 19 July 2006
This study was designed to identify and characterize Na
in guinea pig gastric myocytes under whole-cell patch clamp. After whole-cell con-
figuration was established under 110 mM intracellular Na
holding potential of -60 mV, a large inward current was produced by external 60
channel blockers had little effects on the current (p>0.05). Only TEA (5 mM) inhib-
ited steady-state current to 68±±2.7% of the control (p<0.05). In the presence of K
channel blocker cocktail (mixture of Ba
TEA), a large inward current was activated. However, the amplitude of the steady-
state current produced under [K
pipette solution was replaced with K
er cocktail than under 110 mM [Na
under low Cl-pipette solution, this current was still activated and seemed K
tive, since reversal potentials (Erev) of various concentrations of [K
in current/voltage (I/V) relationship were nearly identical to expected values. R-56865
(10-20 M), a blocker of IK(Na), completely and reversibly inhibited this current. The
characteristics of the current coincide with those of IK(Na) of other cells. Our results
indicate the presence of IK(Na) in guinea pig gastric myocytes.
+]o). This inward current was not affected by removal of external Ca
2+, glibenclamide, 4-AP, apamin, quinidine and
+]o (140 mM) was significantly smaller when Na
+- and Li
+]i. In the presence of K
+in the presence of K
+channel blocker cocktail
Key Words : Muscle, Smooth; Myocytes, Smooth Muscle; Gastrointestinal Tract; Stomach; Na
Current (IK(Na)); Guinea Pigs
Y.C. Kim, J.H. Sim, T.M. Kang, et al.
tude, frequency, and rate of rise of the upstroke potentials (17,
18). Acetylcholine (ACh)-induced inward current (IACh) in GI
smooth muscles is known as Na+permeable channel (19). In
addition, Na+current has been reported in human jejunal
circular smooth muscle (20). Therefore, it is highly likely that
pathways for Na+influx apparently exist in GI smooth mus-
cles. It is known that intracellular Na+concentration in rest-
ingstate reaches less than 10 mM in cardiac and smooth mus-
cle cells (21, 22), and [Na+]i in smooth muscles is increased
or expected to increase by the inhibition of Na+-K+pump
(18, 21). These earlier observations suggest a possibility that
increased level of intracellular Na+might play an important
role in GI smooth muscle. And one of the possibilities is K(Na)
channel. Therefore, this study was designed to prove the exis-
tence of IK(Na) in guinea pig gastric myocytes.
MATERIALS AND METHODS
Preparation of cells
Guinea pigs of both gender, weighing 300-350 g, were
exsanguinated after stunning. All experiments were perform-
ed in accordance with the guidelines for the animal care and
use approved by the Chungbuk National University. The
antral portion of stomach was cut, and the mucosal layer was
separated from the muscle layers in Ca2+-free physiological
salt solution (Ca2+-free PSS). The circular muscle layer was
dissected from the longitudinal layer using fine scissors and
made into small segments (2×3 mm). These segments were
incubated in Ca2+-free PSS for 30 min at 4℃. Then, they
were incubated for 15-25 min at 35℃ in the digestion me-
dium containing 0.1% collagenase (Wako Pure Chemicals,
Osaka, Japan), 0.05% dithiothreitol, 0.1% trypsin inhibitor
and 0.2% bovine serum albumin. Following incubation in
the enzyme solution, the supernatant was discarded. The soft-
ened muscle segments were transferred into Ca2+-free PSS
medium, and tissues were washed repeatedly (4-5 times) with
Ca2+-free PSS medium. Tissues were then gently agitated with
a wide-bore glass pipette to prepare a cell suspension. Isolated
cells were kept at 4℃ in Ca2+-free PSS medium until use.
Experiments were performed at room temperature within 6
hr of harvest of cells.
Voltage-clamp patch experiments
Isolated cells were transferred to a small chamber on the
stage of an inverted microscope (IX-71, Olympus, Tokyo,
Japan). The chamber was perfused with PSS (2-3 mL/min).
Glass pipettes with a resistance of 2-5 M
a giga seal of 5-10 G , by using standard patch clamp tech-
niques (23). Membrane currents were amplified with an axo-
patch-1C or 200B patch-clamp amplifier (Axon Instruments,
California, U.S.A.), and a data were digitized with Digidata
were used to make
1,220 or Digidata 1,322 and stored directly and digitized
on-line using pClamp software (version 5.5.1 or 9.2). Data
were displayed on a digital oscilloscope, pen recorder (Gould,
Cleveland, OH, U.S.A.) and a computer monitor, and data
were analyzed using pClamp 6.0 (pClamp 9.2) and Origin
Solution and drugs
Ca2+-PSS, containing (in mM) NaCl 140, KCl 5, CaCl2 2,
MgCl2 1, glucose 5, and HEPES (N-[2-hydroxyethyl] piper-
azine-N′ -[2-ethanesulphonic acid]) 10, and pH was adjusted
to 7.4 with NaOH. CaCl2 was simply omitted in the Ca2+-
free PSS. Equimolar concentrations of external Na ([Na+]o)
were replaced by K+for various extracellular K+([K+]o). In
some experiments, [Na+]o and [K+]o were replaced by 145
mM N-methyl-D-glucamate chloride (NMDG) or CsCl2.
Pipette solution, containing (mM) KCl 145, GTP (Tris form)
0.1, EGTA (ethylene glycol-bis (2-aminoethyl ether- N,N,
N′ ,N′ -tetraacetic acid) 10, creatine phosphate (CrP, Tris form)
2.5, HEPES 10, ATP (Tris form) 4, MgCl2 5, and pH was
adjusted to 7.3 with TRIZMA. Equimolar concentration of
K+in K+-rich pipette solution was replaced by Li+or Na+for
making Li+- and Na+-rich pipette solution, respectively. For
low Cl-pipette solution, containing Na-gluconate 100, KCl
13, Na2GTP 0.1, Na2ATP 2.5, Na2CrP 2.5, EGTA 10, HE-
PES 10, Mg2ATP 1.5, MgCl2 3.5, K -gluconate 22, pH was
adjusted to 7.3 with TRIZMA. R56865 (N-[1-(4-(4-fluo-
lamine was a kind gift from Janssen Research Foundation,
Beerse, Belgium). All drugs used in this study were purchased
from Sigma (St. Louis, MO, U.S.A.).
Data are expressed as means±standard errors of the mean
(means±SEM). The Student’s t-test was used wherever app-
ropriate to evaluate differences in data. p value less than 0.05
was taken as statistically significant.
Membrane potential was held at -60 mV, and hyperpolar-
izing-ramp pulse, ranging from 80 to -120 mV (-0.05 V/
sec), was applied to cells with 15 sec interval. After the whole-
cell configuration was established, inward current was pro-
duced by increasing the external K+from 4.5 mM to 140
mM. The amplitude of the steady-state inward current was
-47±13.1 pA under K+rich pipette solution (n=4, Fig. 1Aa).
However, significantly large amplitude of the steady-state
inward current was produced by increasing [K+]o (60 mM)
under 110 mM of intracellular Na+concentration ([Na+]i)
(-1,052±145.7 pA, n=5, Fig. 1Ab). Right panel of Fig. 1Ab
+Current in Guinea-pig Stomach
shows the current/voltage (I/V) relationship of Na+-induced
inward current by increasing [K+]o (60 mM) under 110 mM
[Na+]i ([K+]i=35 mM). Reversal potential (Erev) of this cur-
rent in I/V relationship was 12.5 mV and it was close to ex-
pected K+equilibrium potentials (13.6 mV). Fig. 2A shows
I/V relationship of Na+-induced inward current by increasing
[K+]o (60 and 140 mM) under 80 mM [Na+]i. Erev of each
current in I/V relationship was 1 and 19 mV, respectively
(Fig. 2A). Each potential was shifted to rightwards, follow-
ingexpected potentials by increasing [K+]o(60 and 140 mM).
These inward currents which was activated by increasing [K+]o
was blocked by total replacement of external solution with
[NMDG+]o and [Cs+]o, respectively (Fig. 1B).
Effects of K+channel blockers, such as Ba2+, glibenclamide,
140 mM [K
140 mM [K
110 mM [Na
60 mM [K
-60 -300 30 60 90
140 mM [NMDG
60 mM [K
140 mM [Cs
140 mM [K
140 mM [NMDG
60 mM [K
Fig. 1. Na
Whole-cell current was recorded at a holding potential of -60 mV.
is produced by the application of 140 mM [K
shows 60 mM [K
110 mM [Na
In B, Na
ment of [K
+-induced inward current in guinea pig gastric myocytes.
+-rich pipette solution, less than -50 pA of inward current
+]o in Aa. Panel Ab
+]o-induced large inward current produced under
+]i. In the right panel, representative I/V relationship
+-induced inward current activated by 60 mM [K
+-induced inward currents are blocked by total replace-
+]o by 140 mM [NMDG
+]o is shown.
+]o and [Cs
+]o under 110 mM [Na
-120 -90 -60 -300 30 60 90
60 mM K
140 mM K
ControlTEA 5 mM
110 mM110 mM [Na
& low CI-
Fig. 2. Characteristics of Na
was studied. I/V relationship of K
Reversal potentials (Erev) of each current recorded under 60 mM [K
reversal potential recorded was close to calculated one. Panel B shows inhibitory effects of 5 mM TEA on Na
In C, effects of K
[Cl-]i conditions are summarized (see the result for the detail). Averaged results are shown (mean±SEM) and numbers in parentheses
indicate the number of cells examined.
+-induced inward current in guinea pig gastric myocytes. Ionic selectivity of the Na
+-induced inward current under 80 mM [Na
+]o was shifted to rightwards direction under and 140 mM [K
+-induced inward current
+]i is shown in A, where ramp-hyperpolarizing pulse was applied.
+-induced inward currents.
+]i, 110 mM [Li
+channel blockers on Na
+-induced inward currents induced by 140 mM [K
+]o under 110 mM [Na
+]i and low
140 mM [K
140 mM [K
+channel blocker cocktail
Fig. 3. Characteristics of Na
ence of K
pig gastric myocytes. (A) At a holding potential of -60 mV, K
duced inward current was activated by application of 140 mM [K
in the presence K
M), glibenclamide (10 M), TEA (10 mM), 4-AP (10 mM), and
apamin (300 nM)). Panel Ba shows I/V relationship of K
inward current under low Cl-and 110 mM [Na
ship of Fig. 3Ba were plotted against [K
charge carrier of this current. The dotted data was fit very well with
the line which represents the theoretical Ek calculated from Nernst
equation. The obtained data have a slope of 56 mV per 10-fold
change of [K
+-induced inward current in the pres-
+channel blockers and low Cl--pipette solution in guinea
+channel blocker cocktail (mixture of Ba
+]i in the presence
+channel blocker cocktail. In Bb, Erev obtained in I/V relation-
+]o to identify the major
4.5 mM K
30 mM K
90 mM K
140 mM K
140 mM [ ]o
channel blocker cocktail
tetraetylammonium (TEA), 4-aminopyridine (4-AP), apa-
mine, and quinidine, on the steady-state of Na+-induced cur-
rent were studied. Either of Ba2+(100 M), glibenclamide
(10 M), 4-AP (10 mM), or quinidine (3 M) did not block
Na+-induced inward current (p>0.05; data not shown). How-
ever, TEA (5 mM) decreased the steady-state current of Na+-
induced current to 68±2.7% of the control (n=5, p<0.05,
Fig. 2B). Since K(Ca)and KATPchannels are present in GI tract,
Na+-induced inward current was studied in the presence of
diverse K+channel blockers to eliminate the possibility of
contamination with other types of K+channels. In the pres-
ence of K+channel blocker cocktail (mixture of K+channel
blockers using Ba2+[100 M], glibenclamide [10 M], TEA
[10 mM], 4-AP [10 mM], apamine [300 nM], and quinidine
[3 M]; pH was adjusted to 7.4 before use), Na+-dependent
current was still recorded. The amplitude of inward current
with 140 mM [K+]o was -1,063±182.1 pA (Fig. 2C, 3A).
However, small steady-state inward current (-60±38.1 pA)
was shown under Li+-rich pipette solution (n=4, p<0.05; Fig.
2C). It has recently been reported that certain types of KNa
channels (slick and slackchannels) have a Cl-dependence (24).
To evaluate the Cl-dependence of Na+-induced inward cur-
rent in guinea pig gastric myocytes, amplitude of the Na+-
induced inward current was compared using 20 mM Cl-pi-
pette solution. The amplitude of Na+-induced inward current
under 20 mM Cl-and 110 mM [Na+]i in the presence of K-
channel blocker cocktail was -471±86.0 (n=5, Fig. 2C). To
evaluate the ionic selectivity of inward current obtained in the
presence of K+channel blocker cocktail, Erev was also deter-
minedfrom the I/Vrelationship and plotted against logarith-
mic scale of [K+]o (Fig. 3Bb). When the line-fitting was app-
lied to the data points, a slope of recorded data under K+chan-
nelblocker cocktail and low Cl-pipette solution was obtained.
In 3 tested cells, the slope was 52±2.5 mV per 10-fold change
in [K+]o. These results suggest that Na+-induced inward cur-
rent in guinea pig gastric myocytes is selective to K+ions.
Finally, to confirm that Na+-induced inward current is
IK(Na), we studied the effect of R-56865 which is known to
block IK(Na). As shown in Fig. 4A, R-56865 inhibited Na+-
induced inward K+current in a reversible manner. Ten and
twenty M R-56865 inhibited Na+-induced inward current
to 11±5.7 and 4±2.9% of the control (n=3 and 5), respec-
tively (p<0.05, Fig. 4B) in the presence of K+channel block-
ers and low Cl-pipette solution.
Intracellular Ca2+is regarded as one of main regulatory fac-
tor in many biological responses including activation of ion
channels (6). In contrast to Ca2+, Na+has not generally been
considered as an important intracellular messenger to say
nothing of muscular cells. However, since K(Na) channel was
first identified in guinea pig cardiac myocytes, its existence
and importance of [Na+]i have also been reported in various
neuronal cells (11, 12, 15, 16, 25). These facts naturally raise
a question of whether K(Na)channel exists in GI smooth mus-
cle. As can be seen in Fig. 1Aa, increasing [K+]o (140 mM)
failed to produce inward current without Na+in pipette solu-
tion. This is also true when Na+in pipette solution was re-
placed with Li+in the presence of K+channel blocker cock-
tail (Fig. 2C). However, addition of Na+into pipette solution
produced inward current by stimulation of increasing [K+]o.
As can be seen in Fig. 1Ab (110 mM [Na+]i) and 2A (80 mM
[K+]o), increasing [K+]o produced larger inward currents, and
the Erev was moved to rightward direction following the val-
ues expected. However, this current was not affected by pre-
treatment with ouabain (10 M) known to blocker of Na+-
K+pump (data not shown).
Even though K(Na) channel has been reported to exist in the
heart and neurons, its electrophysiological and molecular pro-
perties are poorly understood compared with other K+chan-
nels. Furthermore, characteristics of K(Na) channel, have not
yet been reported in any smooth muscle including GI tract.
To date, two representative molecular identities known as
KNa channel subunits have been reported: Slack and Slickgene
families (24, 26). In both type of KNa channels, TEA (20 mM)
was reported to inhibit KNa channels significantly (24). As
seen in Fig. 2B, TEA (5 mM) significantly inhibited Na+-
induced current in guinea pig gastric myocytes. Since K(Ca)
Y.C. Kim, J.H. Sim, T.M. Kang, et al.
Fig. 4. Effect of R-56865 on Na
under low Cl-pipette solution, K
current is blocked by application of 10 M R-56865 in a reversible manner. In Panel B, inhibitory effects of R-56865 (10 and 20 M) on
+-induced inward current in guinea pig gastric myocytes. (A) In the presence of K
+-induced inward current is activated by application of 140 mM [K
+channel blockers cocktail
+]o at a holding potential of -60 mV. This
+-induced inward current are summarized. The numbers above the columns indicate the number of cells examined.
140 mM [K
+]0 & K
+channel blocker cocktail
R-56865 10 M
ControlR-56365 10 M20 M
and KATP channels are present in GI tract, we tried also to
exclude activation of K(Ca) and KATP channels by high Ca2+
buffering capacity, using 10 mM EGTA and 4 mM ATP, at
holding potential of -60 mV. In addition, to prevent possible
activation of other types of K+channels, we studied [Na+]-
induced current in the presence of K+channel blocker cock-
tail which contained Ba2+(100 M), glibenclamide (10 M),
TEA (10 mM), 4-AP (10 mM), apamine (300 nM), and qui-
nidine (3 M) (Fig. 2C, 3A). In the presence of K+channel
blocker cocktail, Na+-induced inward current was activated,
although the amplitude of the steady state current was reduced.
As shown in Fig. 2C, IK(Na) was further reduced under low Cl-
in the presence of K+channel blocker cocktail. It has recently
been reported that certain types of KNa channels (slick and
slack channels) are Cl-dependent and slick is highly sensitive
to Cl-(27). As shown in Fig. 2C, 3Ba and 4A, the amplitude
of Na+-induced current in the presence of K+channel blocker
cocktail was significantly reduced by low Cl-pipette solution.
However, as shown in Fig. 1B, Na+-induced inward current
was blocked by 140 mM [NMDG+]o and [Cs+]o. Therefore,
it seemed that IK(Na) in guinea pig gastric myocytes might
also be Cl--dependent for its activation.
Ionic selectivity of Na+-induced current was studied under
low Cl-pipette solution in the presence of K+channel blocker
cocktail to eliminate all possible contaminations. As shown
in Fig. 3Bb, the slope of reversal potential obtained versus
[K+]o in the presence of K+channel blocker cocktail by lin-
ear-fitting was 52±2.5 mV per 10-fold change in [K+]o (28).
Finally, Fig. 4 shows reversible inhibitory effect of R-56865
(10 and 20 M) on Na+-induced inward current. These results
are very similar to the results observed in cardiac cells (29,
30). All the above findings suggest that Na+-induced inward
current recorded in our experiment is IK(Na) found in guinea
pig gastric myocytes. For activation of K(Na) channel of car-
diac myocytes in single channel level, it required at least 10-
20 mM [Na+]i(11, 12, 16). A recent report also suggests that
the half-maximal activation of K(Na) channel by Na+occurs
between 7 and 80 mM, depending on cell types and record-
ing conditions in single channel levels (13). Therefore, single
channel study appears to be required in the future to deter-
mine the threshold of [Na+]i for activation of IK(Na) in guinea
pig gastric myocytes.
In cardiac myocytes, it was reported that normal level of
[Na+]i is less than 10 mM (22). Therefore, it is unlikely that
K(Na) channel would ever be activated under normal condi-
tions. Instead, a considerable increase of [Na+]i is possible in
case of a prolonged failure of Na+pumping after the onset
of acute ischemia or during anoxia. Increase of [Na+]i would
cause reversal of Na+-Ca2+exchange due to a reduced driving
force for Na+ions (11, 31, 32). However, the activation of
IK(Na) following intracellular Na+accumulation may set mem-
brane potential to more negative ranges so that Na+-Ca2+ex-
changer may maintain the driving force for Na+influx, there-
by improving Ca2+transport (33). In the case of neurons, [Na+]i
in resting state also ranges between ~4 and 15 mM (27), how-
ever,[Na+]i in neurons can also reach as high as ~100 mM by
stimuli in dendrites (27, 34). Therefore, it has earlier been
suggested that the activation of IK(Na) could be involved in
setting RMP and generating the spindle waves of neurons
(15, 16, 35). As known well, there are several Na+influx path-
ways in GI tract such as Na+channel, IACh and Na+-K+pump
(18-21). Therefore, IK(Na) may play an important physiologi-
cal role in the regulation of membrane potential, hence the
motility of GI tract. Since there has been no report until now
on the identification of K(Na)channel in either GI tract or whole
smooth muscle research field, the present study is the first
report to prove the existence of IK(Na) in guinea pig gastric
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