RAPID COMMUNICATION
Role of HERG-like K+ currents in
opossum esophageal circular smooth muscle
Hamid I.
Akbarali1,
Hemant
Thatte1,
Xue Dao
He1,
Wayne R.
Giles2, and
Raj K.
Goyal1
1 Center for Swallowing and
Motility Disorders, Harvard Medical School, West Roxbury Veterans
Affairs Medical Center, West Roxbury, Massachusetts 02132; and
2 Department of Physiology and
Biophysics, University of Calgary, Calgary, Alberta,
Canada T2N 4N1
 |
ABSTRACT |
An inwardly
rectifying K+ conductance closely
resembling the human ether-a-go-go-related gene (HERG) current was
identified in single smooth muscle cells of opossum esophageal circular
muscle. When cells were voltage clamped at 0 mV, in isotonic
K+ solution (140 mM), step
hyperpolarizations to
120 mV in 10-mV increments resulted in
large inward currents that activated rapidly and then declined slowly
(inactivated) during the test pulse in a time- and voltage- dependent
fashion. The HERG K+ channel
blockers E-4031 (1 µM), cisapride (1 µM), and
La3+ (100 µM) strongly inhibited
these currents as did millimolar concentrations of
Ba2+. Immunoflourescence staining
with anti-HERG antibody in single cells resulted in punctate staining
at the sarcolemma. At membrane potentials near the resting membrane
potential (
50 to
70 mV), this
K+ conductance did not inactivate
completely. In conventional microelectrode recordings, both E-4031 and
cisapride depolarized tissue strips by 10 mV and also induced phasic
contractions. In combination, these results provide direct experimental
evidence for expression of HERG-like
K+ currents in gastrointestinal
smooth muscle cells and suggest that HERG plays an important role in
modulating the resting membrane potential.
human ether-a-go-go; resting membrane potential; cisapride; inward
rectifier
 |
INTRODUCTION |
IN MANY EXCITABLE TISSUES the
K+ conductance that is responsible
for the resting potential exhibits inward rectification (12). Inwardly
rectifying K+ currents
(Kir) exhibit high conductance
at negative potentials but greatly reduced conductance at positive
potentials, thus avoiding short circuiting of the action potential. In
smooth muscle, Kir belonging to
the Kir 2.1 family of
K+ channels have been identified
in small diameter resistance blood vessels (6) but not in visceral
smooth muscle. Isolated visceral smooth muscle cells, in physiological
solutions, express only very small background
K+ currents (>20 pA). In most
cases, this precludes detailed characterization of the
K+ channels that are responsible
for maintaining the resting potential. Partly for this reason, the
question of whether a Kir
contributes to the resting potential of these smooth muscle remains unresolved.
Recent findings have drawn attention to the possible role of a novel
inwardly rectifying K+ channel,
the human ether-a-go-go-related gene (HERG)
K+ channel, in modulating the
resting membrane potential (RMP) associated with cell cycle changes,
and in the setting of RMP of microglia (3, 24). HERG
K+ channels have six
transmembrane-spanning regions and therefore are distinct from other
inward rectifiers that have only two transmembrane-spanning regions
(21, 23). In cardiac myocytes, the HERG channel encodes for a rapidly
activating delayed rectifier K+
current (IKr)
(17). Mutations of HERG, or use of HERG channel blockers have been
shown to cause cardiac abnormalities such as the long Q-T
syndrome (8, 17). Interestingly, the gastrointestinal prokinetic agent,
cisapride, was recently reported to block heterologously expressed HERG
channels (14, 15), consistent with its proarrhythmic cardiac effects.
In the present study, we provide evidence for the presence of HERG-like
K+ current in esophageal circular
smooth muscle, define its role in setting RMP, and demonstrate that
effects of cisapride in the esophagus are due to inhibition of
HERG-like K+ currents.
 |
METHODS |
Cell isolation and electrophysiology.
Single smooth muscle cells from the distal part of the subdiaphragmatic
esophagus of the opossum (Didelphis
virgiana) were prepared by enzymatic dissociation as
described previously (1). Patch-clamp experiments were done using the
standard whole cell configuration, with a pipette solution containing
(in mM) 100 potassium aspartate, 30 KCl, 5 HEPES, 5 ATP-Na2, 1 MgCl2, 0.1 GTP, and 5 EGTA. The pH
was adjusted to 7.2 with KOH. The pipette resistance was 3-5 M
.
The cells were initially perfused with a normal HEPES-buffered solution
containing (in mM) 135 NaCl, 5.4 KCl, 0.33 NaH2PO4,
5 HEPES, 0.8 MgCl2, 2 CaCl2, and 5.5 glucose (pH 7.3 with NaOH). The isotonic K+
solution that was used for characterization of HERG
K+ currents contained (in mM) 140 KCl, 0.1 CaCl2, 1 MgCl2, 5 HEPES, 5 tetraethylammonium, 3 4-aminopyridine, and 5.5 glucose. The pH was
adjusted to 7.3 with KOH. Recordings were filtered at 1 kHz and sampled
at 2.5 kHz. The voltage-clamp amplifier was an Axopatch 200 A (Axon
Instruments). Capacitative transients were not electronically canceled.
Data acquisition and analyses were preformed using pCLAMP 6 software.
Figures 1-4 were prepared using Sigmaplot 4.0 and Origin
5.0.
In some experiments, intracellular membrane potentials were recorded,
using microelectrodes filled with 3 M KCl (7), from smooth muscle cells
of circular muscle strips obtained from distal esophagus. Atropine (1 µM), guanethidine (3 µM), and desensitizing concentrations of
substance P (1 µM) were present in the perfusate. For tension
recordings, circular smooth muscle strips were attached to a force
transducer (Grass) in 3-ml organ baths. Tension was measured in the
presence of atropine (1 µM) and tetrodotoxin (1 µM).
Immunostaining. Single smooth muscle
cells from the opossum esophagus were fixed in 3.7% formaldehyde for
30 min at room temperature and permeabilized by adding 0.1% Triton
X-100 in PBS. Nonspecific binding sites were blocked by incubating
cells with 10% goat serum for 1 h at room temperature and were washed
and then treated with rabbit anti-HERG antibody (1:100 dilution) for 90 min. The cells were washed twice in PBS and then incubated with
polyclonal fluorescein isothiocyanate (FITC)-conjugated donkey
anti-rabbit antibody (1:100 dilution) for 1 h. Cells were subsequently
washed twice with PBS, mounted on slides, and imaged using an
epifluorescence confocal microscope (MRC 1024; Bio-Rad), at ×80
magnification. To further investigate the specificity of the anti-HERG
antibody, cells were treated with nonspecific IgG for 30 min at room
temperature before incubation with the primary antibody. In another
control, cells were labeled with FITC-conjugated donkey anti-rabbit
antibody in the absence of primary antibody. In this experiment,
epifluourescence was barely visible. Nonspecific binding was <10%,
as ascertained by photon counting of these cells.
The anti-HERG antibody was a generous gift of Dr. Jeanne Nerbonne
(Washington University, St. Louis, MO). Similar staining was also
obtained using rabbit anti-HERG antibody from Alomone Labs (Jersualem,
Israel). E-4031 was purchased from Wako Chemical Industries (Osaka,
Japan). Cisapride was a generous gift from Jannsen Research Foundation
(Beerse, Belgium). All other reagents were purchased from Sigma (St.
Louis, MO).
 |
RESULTS |
Kir in esophageal cells.
Single smooth muscle cells isolated from the opossum esophageal
circular muscle were perfused in
high-K+ solution (140 mM
K+) to enhance the size of the
K+ currents and hence permit
unambiguous identification and quantitative analysis.
Ca2+-activated
K+ currents, transient outward
K+ currents, delayed rectifiers,
and ATP-sensitive K+ currents were
blocked by including tetraethylammonium (10 mM), 4-aminopyridine (3 mM), and low extracellular
Ca2+ concentration (0.1 mM) to all
superfusing solutions and by adding a high ATP concentration (5 mM) to
the pipette solutions. Under these conditions, with the Nernst
potential for K+
(EK) set at 0 mV, activation of K+ conductance
produces inward currents. Hyperpolarization from 0 mV induced large
transient inward currents (Fig.
1A).
The kinetics of both activation and inactivation exhibited voltage
dependence. The time constant for activation (when described by single
exponential fits) decreased from 21 ± 2 ms at
60 mV to 8 ± 0.6 ms at
120 mV (n = 6).
At potentials negative to approximately
60 mV, a substantial
inactivation occurred, resulting in the crossover of the currents.
These currents closely resemble those recorded from microglia and
pituitary cells (5, 24) in which HERG has been shown to be the
underlying K+ conductance.
Families of transmembrane currents from the holding potential of 0 mV
were recorded from eight cells and were normalized to peak currents at
120 mV. This current-voltage curve (Fig. 1B) demonstrates the presence of a
Kir in these esophageal circular muscle cells.

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Fig. 1.
Inward rectifying K+ currents in
opossum esophageal smooth muscle cells. Whole cell currents were
measured in isotonic K+ solutions.
A: family of currents recorded from
holding potential of 0 mV. Voltage steps were applied in 10-mV
increments from 120 to +30 mV. Note that hyperpolarization
results in large inward currents that relax (inactivate) slowly.
B: peak current-voltage relationship.
Currents were normalized to peak amplitude at 120 mV and
represent mean amplitude in 8 different cells.
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Pharmacological properties of the HERG
current. The pharmacological profile of the currents in
isotonic K+ also provided evidence
for the presence of HERG-like K+
currents in esophageal smooth muscle. To examine whether this inwardly
rectifying current may result from the expression of HERG-like
K+ current, known HERG blockers
were applied. The methanesulfonanilide E-4031 strongly
inhibits HERG K+ channels in the
heart (20). Figure
2A shows
that, in the esophageal cells, 1 µM E-4031 completely abolished the
hyperpolarization-activated currents in isotonic
K+ solution. The
IC50 for this inhibition was 450 ± 53 nM (n = 5), which is within
the range reported for inhibition of the HERG-like K+ channel (20, 24). Figure
2B shows that the prokinetic agent, cisapride, also strongly blocks the HERG-like
K+ currents as it does in
mammalian cells transfected with the HERG channel (14, 15). Families of
current traces from one cell are shown in control and after 3 min of
exposure to cisapride (1 µM). In the heart and in microglia cells,
La3+ has been reported to block
HERG currents (18). As shown in Fig.
2C,
La3+ (100 µM) also markedly
abolished the HERG currents in esophageal circular smooth muscle. In
the final set of experiments in which inhibitors were used to
characterize the K+ currents,
BaCl2 was applied. It is known
that conventional inwardly rectifying
K+ currents (e.g.,
Kir 2.1) are blocked completely by
very small concentrations (10-100 µM) of
Ba2+ (12). As shown in Fig.
2D, 1 mM
Ba2+ only partially abolished
these currents, whereas 10 mM Ba2+
resulted in substantial block. These studies demonstrate that the
inwardly rectifying currents in smooth muscle strongly resemble HERG-like K+ currents.

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Fig. 2.
Pharmacological profile of inwardly rectifying
K+ currents and immunostaining in
esophageal cells. A: effect of E-4031
(1 µM) on K+ currents. Cell was
hyperpolarized to 120 mV from 0 mV. E-4031 (3-min perfusion)
markedly inhibited inward currents. B:
effect of cisapride (1 µM). Family of inward currents were elicited
as shown in voltage protocol. Cisapride (1 µmM) significantly reduced
human ether-a-go-go-related gene (HERG)-like
K+ currents.
C: effect of
La3+. Cell was hyperpolarized to
100 mV. In presence of
La3+, voltage step to 100
mV resulted in almost complete inhibition.
D: effect of
Ba2+. Inward currents were
elicited by hyperpolarization to 90 mV from holding potential of
0 mV in absence and presence of 1 mM
Ba2+ and then 10 mM
Ba2+. Each concentration of
Ba2+ was equilibrated for 3 min
before voltage-clamp measurements. Note that, in 10 mM
Ba2+, stepping back to 0 mV
elicits inward Ba2+ currents
through L-type Ca2+ channels.
E: immunoflourescence due to anti-HERG
antibody staining in single smooth muscle cell. Confocal image
(×80 magnification) shows punctate staining distributed over
entire cell surface.
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|
The presence and localization of HERG channels in smooth muscle
myocytes were confirmed with immunofluorescence staining. As shown in
Fig. 2E, a punctate fluorescence
pattern was observed on the sarcolemma of the single cells. This
pattern of staining closely resembles that observed in cardiac tissue
(4).
As a further test of the similarity of this
K+ conductance to HERG-like
K+ currents, the biophysical
mechanism responsible for the observed inward rectification in
esophageal cells was examined. In heterologously expressed HERG
channels from mammalian heart, it has been shown that the mechanism of
the inward rectification is voltage-gated fast inactivation (19). This
possibility was evaluated by measuring the instantaneous
current-voltage curve. Cells were briefly hyperpolarized to
120
mV to remove inactivation and then stepped back to test potentials of
120 to +30 mV (Fig.
3A).
The instantaneous current-voltage relationship, which was measured by
extrapolation of single exponential fits of the tail currents to the
beginning of the test pulse, was approximately linear (Fig.
3B). A plausible explanation for this finding, based on previous work (19, 21), is that, in the absence
of time-dependent inactivation, HERG
K+ channels do not exhibit inward
rectification. At depolarized potentials these
K+ channels enter inactivated
states very quickly, thus resulting in strong inward rectification.

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Fig. 3.
Mechanism of inward rectification and steady-state availability of HERG
currents. Biophysical mechanism of inward rectification was studied
using a 2-step voltage protocol illustrated at
top. A 30-ms prepulse was applied to
120 mV from the holding potential (0 mV), membrane potential was
then stepped back to selected test potentials (from 120 to
+30 mV in 10-mV increments). Instantaneous current amplitude was
measured by fitting single exponentials to tail currents and
extrapolating to beginning of test pulse.
B: average instantaneous
current-voltage relationship was normalized to amplitude of currents at
120 mV (n = 5).
C: steady-state voltage dependence of
availability. Two-step voltage protocol was applied as illustrated at
top. A long prepulse (14 s) to
selected membrane potentials (+20 to 120 mV) was applied followed by
100-ms test pulse to 120 mV. D:
amplitude of test current was plotted against prepulse potential,
resulting in steady-state availability curve that was fit with a
Boltzman relationship of the form
I/Imax = 1/{1 + [exp(V0.5 V)/k]},
where I is curent and
V is voltage.
E: voltage dependence of
noninactivating or window current. Currents were measured at end of
prepulse from experiments as shown in
C. Maximum window currents were
observed between 50 and 70 mV
(n = 5). , Currents measured at end
of prepulse in presence of cisapride (1 µM).
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Removal of intracellular Mg2+ from
the pipette solution did not prevent inward rectification in esophageal
cells (data not shown), providing further evidence that the inward
rectification due to expression of, e.g., the
Kir 2.1 family of
K+ channels was not responsible
(13, 19).
To determine the steady-state voltage dependence of availability, cells
were held at membrane potentials ranging from +20 to
120 mV for
14 s (Fig. 3C). At the end of this
prepulse, a 100-ms test pulse of
120 mV was applied. Normalized
peak inward test currents plotted against the prepulse potential
demonstrate the steady-state voltage dependence of availability of the
K+ conductance (Fig.
3D). The voltage at which one-half
the channels are available for activation was
72 mV, and this
Boltzmann relationship had a slope factor of 6.8.
Close inspection of Fig. 3C shows that
a noninactivating current is present at the end of the prepulse.
Current-voltage relationships of these "window currents" were
measured by plotting the amplitude of the noninactivating current vs.
the applied voltage. As shown in Fig.
3E, this relationship showed a
U-shaped dependence on voltage, with the maximal steady-state currents
being recorded near the resting membrane potential of smooth muscle
cells (between
70 and
50 mV). The noninactivating
currents were significantly blocked by 1 µM cisapride (Fig.
3E).
HERG currents in resting potential.
The presence of a noninactivating
K+ current at membrane potentials
near the resting potential (Fig. 3E)
suggest a role for the HERG-like
K+ currents in the setting of RMP.
To evaluate this possibility, we examined the effects of HERG blockers
on the membrane potential and contractility in in vitro esophageal
muscle strip preparations. E-4031 at concentrations of 100 nM produced
a small tonic contraction. At higher concentrations (1-3 µM)
spontaneous phasic contractions were elicited (Fig.
4A).
Recordings of intracellular membrane potential showed that both
E-4031(3 µM) and cisapride (5 µM) depolarized the membrane
potential by ~10 mV (Fig. 4B).
These observations provide further support for the essential role of
the HERG channel in regulation of resting membrane potential and
mechanical responses of the esophageal circular muscle.

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Fig. 4.
In vitro recordings from esophageal muscle strips.
A: recording of developed tension from
isolated esophageal muscle strip in organ bath. Application of E-4031
(0.1 µM) resulted in a small rise in tension. At higher
concentrations (1 µM) phasic contractions were obtained.
B: microelectrode recordings from
esophageal muscle strips. Application of E-4031 (3 µM;
top) depolarized by 7 mV.
Bottom: cisapride (5 µM) depolarized
muscle segments by ~11 mV.
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|
 |
DISCUSSION |
These results provide pharmacological, biophysical and
immunohistochemical evidence for the expression of HERG-like
K+ conductance in opossum
esophageal smooth muscle cells and suggest a potential role for HERG in
regulating resting membrane potential in these cells. The
electrophysiological characteristics of this Kir in esophageal cells strongly
resembles that of the HERG-like K+
currents previously described in
GH3 cells, neuroblastoma cells, and microglia, as well as in heterologously expressed HERG channels in
Xenopus oocytes (3, 5, 21, 24).
Previous publications have established that this type of
K+ conductance can be identified
consistently when isotonic extracellular K+ concentrations
([K+]o)
are used. HERG currents exhibit marked time- and voltage-dependent inactivation and are blocked by methanesulfonanilides such as E-4031
and by relatively high concentrations of
Ba2+. Each of these properties was
observed in our study of the inwardly rectifying HERG-like
K+ current in the opossum
esophageal cells.
The inward rectification of the HERG is thought to be due to a
fast-inactivation mechanism at positive potentials (19). This type of
K+ conductance underlies the
"rapid" component of the delayed rectifier current in the heart,
and it defines its biophysical properties as a repolarizing current.
Thus, during an action potential, maximal currents through HERG
channels occur soon after the membrane begins to repolarize, as these
channels recover from the inactivated state (21). In esophageal smooth
muscle cells, as is the case of microglia and neuroblastoma cells (3,
24), HERG-like K+ currents
contribute to the resting potential. Our data (Fig. 3E) demonstrate that the
noninactivating current is maximal near the resting potential of smooth
muscle cells i.e.,
70 to
50 mV. The conductance at
60 mV was ~25-30% of the maximal conductance at
120 mV. Because, in physiological solutions (5.4 mM
K+), this
K+ conductance will be scaled down
by the square root of the changes in
[K+]o,
peak currents at
60 mV under physiological conditions will be
approximately fivefold smaller than those shown in Fig. 1. Thus these
currents will measure only ~20 pA near the resting potential.
However, in the setting of a high input resistance (5-10 G
), a
20-pA current can significantly modulate the resting potential.
HERG channel blockers depolarized muscle segments and induced
contractions, further suggesting a role of HERG-like
K+ currents in regulating resting
potential. The gastrointestinal prokinetic agent cisapride (1 µM)
completely blocks the HERG-like K+
currents in these smooth muscle cells (Fig.
2D). In cells transfected with the
HERG channel, the IC50 for
cisapride ranges from 6 to 45 nM (14, 15). In addition to its effects
on the 5-hydroxytryptamine receptors, cisapride has been
shown to have direct stimulating effects on gastrointestinal smooth
muscle (20a). Cisapride also significantly blocked the noninactivating currents.
Several types of K+ channels are
suggested to be involved in the control of the resting potential in
gastrointestinal smooth muscle. These include intermediate-conductance
Ca2+-activated
K+ channels (22,), delayed
rectifier K+ currents (10),
transient outward K+ currents (2),
and ATP-sensitive K+ channels
(11). The results presented here strongly support an essential role of
HERG-like K+ currents in
regulating the electrophysiological and mechanical activity of
gastrointestinal smooth muscle.
 |
ACKNOWLEDGEMENTS |
This work was supported by National Institute of Diabetes and
Digestive and Kidney Diseases Grants DK-46367 (H. I. Akbarali) and
DK-31098 (R. K. Goyal), a Veterans Affairs Merit Award (R. K. Goyal),
the Canadian Medical Research Council, the Heart and Stroke Foundation
of Canada, and the Alberta Heritage Foundation for Medical Research (W. R. Giles).
 |
FOOTNOTES |
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: H. I. Akbarali,
Research 151, West Roxbury VA Medical Center, 1400 VFW Parkway, West
Roxbury, MA 02132 (E-mail: hakbarali{at}hms.harvard.edu).
Received 22 July 1999; accepted in final form 3 September 1999.
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