Departments of 1 Metabolism and Clinical Nutrition and of 2 Internal Medicine, Faculty of Medicine, and 3 Faculty of Integrated Human Studies, Kyoto University, Kyoto 606, Japan
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ABSTRACT |
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The effect of
metabolic inhibition on the blocking of -cell ATP-sensitive
K+ channels
(KATP channels) by glibenclamide
was investigated using a patch-clamp technique. Inhibition of
KATP channels by glibenclamide was
attenuated in the cell-attached mode under metabolic inhibition induced
by 2,4-dinitrophenol. Under a low concentration (0.1 µM) of ATP
applied in the inside-out mode,
KATP channel activity was not
fully abolished, even when a high dose of glibenclamide was applied, in
contrast to the dose-dependent and complete
KATP channel inhibition under 10 µM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic
agent, inhibits KATP channel
activity in a dose-dependent manner and completely blocks it, even
under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel
(Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2,
unlike glibenclamide. Thus, KATP
channel inhibition by glibenclamide is impaired under the condition of
decreased intracellular ATP in pancreatic
-cells, probably because
of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.
sulfonylurea receptor; glibenclamide; intracellular metabolism
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INTRODUCTION |
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ATP-SENSITIVE K+
channels (KATP channels) have the
unique characteristic of control by intracellular metabolism, an
elevation of the intracellular ATP concentration or ATP/ADP ratio
inhibiting the activity of the channels. Functional
KATP channels have been identified
most frequently in brain, cardiac and skeletal muscle, kidney, and
pancreatic -cells (3).
Closure of the KATP channels plays
a key role in the insulin secretory mechanism of pancreatic -cells,
depolarizing the cell membrane and promoting
Ca2+ influx through the
voltage-dependent Ca2+ channels.
The resulting elevation of intracellular
Ca2+ concentration triggers
exocytosis of the insulin secretory granules (2). Sulfonylureas, which
have been used clinically as a potent hypoglycemic agent for
non-insulin-dependent diabetes mellitus (NIDDM), strongly inhibit
KATP channel activity by binding
to the high-affinity receptor protein (sulfonylurea receptor; SUR) (4).
The recent molecular cloning of SUR in pancreatic
-cells (SUR1) (1)
revealed the KATP channel to be
composed of at least two subunit molecules, SUR1 and a member of the
inward rectifier K+ channel family
(Kir6.2) (16). The mechanism of signal transmission between these
molecules, however, is still unknown.
The KATP channels of cardiac
muscle have been extensively investigated electrophysiologically. They
have been shown to be activated by intracellular metabolic suppression
and blocked by sulfonylureas (3, 6), similarly to those in pancreatic
-cells. In cardiomyocytes, however, it has been reported that the
sulfonylurea sensitivity of channel inhibition is decreased during
metabolic stress induced by a metabolic inhibitor, 2,4-dinitrophenol
(DNP) or carbonyl cyanide
p-(trifluoromethoxy)-phenylhydradone
(8, 22, 30). This suggests a defect between sulfonylurea binding to SUR
and KATP channel closure in
cardiomyocytes, such as decreased affinity of sulfonylurea binding to
SUR, impairment in signal transmission between SUR and the
K+ channel subunit (Kir), or
functional modifications of Kir.
We have investigated in the present study the effect of intracellular
metabolic inhibition on the suppression of -cell
KATP channel activity by
glibenclamide, a potent blocker of these channels among sulfonylurea
derivatives. The inhibitory effect on channel activity was markedly
decreased during metabolic inhibition in pancreatic
-cells,
similarly to findings in cardiomyocytes. This phenomenon was analyzed
by direct measurement of single-channel activities in the cell-attached
and inside-out configurations of a patch-clamp technique and by a
receptor binding study of SUR1 and Kir6.2.
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METHODS |
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Cell preparation. Islets of Langerhans were isolated from male Wistar rats by a collagenase digestion technique. Dispersed islet cells were prepared for electrophysiological experiments and binding studies. Isolated islets were dispersed using 0.25% trypsin and 1 mM EDTA solution (GIBCO BRL, Grand Island, NY), as previously reported (21). Dispersed islet cells were suspended in RPMI 1640 medium supplemented with 10% fetal calf serum, 100 U/ml penicillin, and 0.1 mg/ml streptomycin. They were cultured on small glass coverslips (15 × 4 mm) overnight at 37°C in a humidified incubator gassed with 95% air-5% CO2. Individual coverslips were transferred to the test chamber and placed on an inverted microscope for patch-clamp experiments.
Electrophysiology.
Single-channel recordings of KATP
channel activity were performed in the cell-attached and inside-out
configurations of the patch-clamp technique. Patch pipettes (resistance
2-5 M) were pulled from borosilicate glass capillaries, coated
with Sylgard (Dow Corning, Midland, MI), fire polished, and filled with
a pipette solution containing (in mM) 140 KCl, 2 CaCl2, and 5 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) (pH 7.4 with KOH). The bath solution for cell-attached experiments was composed of (in mM) 135 NaCl, 5 KCl, 5 CaCl2, 2 MgSO4, and 5 HEPES (pH 7.4 with
NaOH). For inside-out experiments, the composition of the bath
(intracellular) solution was (in mM) 135 KCl, 10 NaOH, 0.1 CaCl2, 2 MgSO4, 1 ethylene
glycol-bis(
-aminoethyl ether)-N,N,N',N'-tetraacetic
acid, 5 HEPES, and 0.1 µM K2ATP
(pH 7.4 with KOH). A small amount of
K2ATP (0.1 µM) was added to the control bath solution immediately before use to prevent slowing down of
KATP channels (9).
Electrophysiological experiments were performed at room temperature
(24-26°C).
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[3H]glibenclamide and [3H]cibenzoline binding study. The displacing effect of glibenclamide on SUR binding was assessed using freshly dispersed islet cells. Islet cells were incubated for 2 h at room temperature in 3-(N-morpholino)propanesulfonic acid (MOPS) buffer (58.1 mM MOPS, 0.116 mM CaCl2, pH 7.4 with NaOH) containing 2 nM [3H]glibenclamide (50.9 Ci/mM, NET-1024, NEN, Boston, MA) in the presence of varying concentrations of nonradioactive glibenclamide. Binding was terminated by rapid filtration through Whatman GF/C filters followed by washing three times with 5 ml of ice-cold distilled water. Radioactivity of filters was counted in 10 ml of an aqueous scintillation cocktail (Aquasol-2, NEN). Results were expressed as the percent radioactivity of bound [3H]glibenclamide that remained after addition of nonradioactive compound.
On the other hand, the amount of specific binding of [3H]glibenclamide and [3H]cibenzoline was assessed using SUR1 or Kir6.2 proteins expressed in COS1 cells. SUR1- or Kir6.2-expressed cell membranes were incubated in MOPS buffer containing 2 nM [3H]glibenclamide, in the absence or presence of 1 mM nonradioactive glibenclamide, or 20 nM [3H]cibenzoline in the absence or presence of 100 mM nonradioactive cibenzoline. The specific binding of [3H]glibenclamide or [3H]cibenzoline was calculated by subtracting nonspecific binding from total radioactive compounds. Protein content was measured by the Lowry method.Chemicals. [3H]cibenzoline (8.0 Ci/mM) and cibenzoline were generously donated by Fujisawa Pharmaceutical (Osaka, Japan). Glibenclamide (Hoeschst Japan, Tokyo, Japan) and cibenzoline were prepared as stock solutions in dimethyl sulfoxide at the concentrations of 1 mM and 1 M, respectively. Each stock solution was further diluted with the solutions immediately before use to the final concentration given in the text. K2ATP was purchased from Sigma Chemical (St. Louis, MO); DNP, 2-deoxy-D-glucose (DG), oligomycin, and other agents were purchased from Nacalai Tesque (Kyoto, Japan).
Statistical analysis. Results were expressed as means ± SE. Statistical significance was evaluated by unpaired and paired Student's t-test, and P < 0.05 was considered significant.
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RESULTS |
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Effect of DNP on blocking of KATP
channels by glibenclamide.
KATP channel activities were
consistently observed in the inside-out patch membranes excised from
single -cells. The current-voltage curve showed inward
rectification, and the unitary conductance of
KATP channels was 61.4 ± 0.7 pS
(n = 5), similar to that of KATP channels in pancreatic
-cells reported previously (3). KATP channel responsiveness to
glibenclamide was examined in the cell-attached configuration in the
absence or presence of 100 µM DNP. As shown in Fig.
1A,
glibenclamide inhibited KATP
channel activity dose dependently, and 100 nM and 1,000 nM
glibenclamide completely eliminated
KATP channel activity in the
absence of DNP. The dose-response curve of
KATP channel inhibition by
glibenclamide, which was well fitted to the Hill equation (3),
exhibited an IC50 of 3.0 nM and a
Hill coefficient of 0.7 (Fig. 1C),
values similar to those reported previously (28). In the presence of 100 µM DNP, however, KATP
channel activity was not fully suppressed by 100 nM glibenclamide, and
complete inhibition was apparent only at a concentration of 1,000 nM
(Fig. 1B). One hundred micromoles of
DNP shifted the dose-response curve of
KATP channel inhibition to the
right (Fig. 1C).
KATP channel activities were not
reduced in the range of 0.01-10 nM glibenclamide and were
completely inhibited by a high concentration of 1,000 nM glibenclamide
in the presence of 100 µM of DNP. Fitting to the Hill equation
yielded an IC50 of 51.3 nM and a
Hill coefficient of 2.0. Other metabolic inhibitors, DG and oligomycin,
also showed a similar attenuation of glibenclamide-induced inhibition
of KATP channel activity. Under 20 mM DG plus 2.0 µg/ml oligomycin, 10 nM glibenclamide did not affect
channel activities [Po/Poc = 0.90 ± 0.08 (n = 9), a result not
significantly different from corresponding control], which were
suppressed by 100 nM and completely inhibited by 1,000 nM glibenclamide
[0.08 ± 0.03 (n = 12) and 0.00 ± 0.00 (n = 5), a result that was
significantly different from corresponding control;
P < 0.01, respectively]. Each
value was similar to one under DNP [not significantly different vs. 0.96 ± 0.04 (n = 5), 0.21 ± 0.09 (n = 10), and 0.02 ± 0.01 (n = 7) in 10, 100, and 1,000 nM
glibenclamide under DNP, respectively].
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Comparison of blocking of KATP channels
by glibenclamide in 10 and 0.1 µM ATP.
To examine the effect of decreased ATP on the blocking of
KATP channels by glibenclamide,
the channel activities were recorded in the inside-out configuration at
70 mV in the presence of 10 or 0.1 µM ATP. As shown in Fig.
2,
A and
C, glibenclamide in the range of
0.1-1,000 nM inhibited KATP
channel activities dose dependently in the presence of 10 µM ATP, and
the inhibition curve was fitted to the Hill equation with an
IC50 of 5.6 nM and a Hill
coefficient of 0.8. On the other hand, in the presence of 0.1 µM ATP,
glibenclamide failed to abolish
KATP channel activities, even at
the high concentration of 1,000 nM (Fig. 2,
B and
C). Figure
2D shows the effect of DNP on
KATP channel activity in the
inside-out patch membrane. DNP itself did not affect
KATP channel activities directly
[Po/Poc = 1.01 ± 0.04 (n = 4), not
significant vs. control].
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Effect of DNP on [3H]glibenclamide binding for pancreatic islet cells. Figure 3 shows the effect of DNP on the displacement of [3H]glibenclamide bound to pancreatic islet cells by nonradioactive glibenclamide. The displacement of [3H]glibenclamide by nonradioactive glibenclamide after incubation in the presence of 100 µM DNP was not significantly different from that in the absence of DNP.
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Effect of DNP on blocking of KATP
channels by cibenzoline.
Cibenzoline, a class Ia antiarrhythmic agent, is known to induce
sporadic hypoglycemia as an extracardiac side effect (11, 15, 18) and
has been reported to stimulate insulin secretion from pancreatic
-cells (5). Recently, Kakei et al. (19) and we (17) both reported
that cibenzoline blocks KATP
channels in pancreatic
-cells. We suggested further that the binding
site of cibenzoline might be different from that of glibenclamide (17). We have investigated the effect of DNP on cibenzoline-induced KATP channel inhibition in the
cell-attached configuration. Cibenzoline suppressed
KATP channel activity dose
dependently and completely blocked
KATP channels at 1,000 µM (Fig.
4A). The
dose-response curve of this inhibition was well fitted to the Hill
equation, with an IC50 of 41.5 µM and a Hill coefficient of 0.8 (Fig.
4C), values similar to those
reported previously (17). In contrast to the effect of glibenclamide,
even in the presence of 100 µM DNP,
KATP channel activity was
suppressed dose dependently by cibenzoline and was completely abolished
by 1,000 µM cibenzoline (Fig. 4B).
The dose-dependent inhibition curve of cibenzoline under DNP
(IC50, 40.7 µM; Hill
coefficient, 1.1) was almost identical to that under the condition of
intact intracellular metabolism (Fig.
4C). Moreover, cibenzoline elicited
a similar effect of channel inhibition even under DG plus oligomycin
[Po/Poc = 0.32 ± 0.06 (n = 7) and 0.01 ± 0.00 (n = 7) in 100 µM and 1,000 µM cibenzoline under DG plus oligomycin, respectively, not
significantly different from 0.26 ± 0.09 (n = 7) and 0.01 ± 0.01 (n = 8) under DNP].
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Comparison of blocking of KATP channels by cibenzoline in 10 and 0.1 µM ATP. Dose-dependent inhibitions of KATP channel activity by cibenzoline were observed in the presence of both 10 µM and 0.1 µM ATP in the inside-out configuration (Fig. 5, A and B). As shown in Fig. 5C, the inhibition curves by cibenzoline were the same in both conditions (IC50, 2.2 µM and 1.9 µM; Hill coefficient, 0.8 and 0.8, in 10 µM and 0.1 µM ATP, respectively) and similar to those described previously (17).
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Comparison of [3H]glibenclamide and [3H]cibenzoline binding to SUR1- or Kir6.2-expressed cells. Figure 6 shows [3H]glibenclamide and [3H]cibenzoline binding to SUR1 or Kir6.2 proteins expressed in COS1 cells. As shown in Fig. 6A, [3H]glibenclamide specifically bound only to SUR1 (1.13 ± 0.07 pmol/mg protein) and not to Kir6.2 or control. On the other hand, the specific binding of [3H]cibenzoline to Kir6.2-expressed cell membranes was more significant than to SUR1-expressed or control membranes (42.9 ± 0.61 pmol/mg protein in Kir6.2 vs. 36.4 ± 0.74 and 34.3 ± 1.08 in SUR1-expressed and control cell membranes, respectively; P < 0.01, Fig. 6B). There was no significant difference in [3H]cibenzoline binding between SUR1-expressed and control cell membranes.
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DISCUSSION |
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The present study shows that -cell
KATP channel inhibition by the
potent channel blocker glibenclamide is attenuated during intracellular
metabolic inhibition by DNP. Moreover, the dose-response curve for
channel inhibition by glibenclamide shifts upward at a lower
concentration of intracellular ATP in the inside-out configuration, and
DNP itself had no effect on KATP
channel activity. On the other hand, the binding affinity of
glibenclamide was found to be unaltered under metabolic inhibition.
These results suggest the putative impairment in signal transmission
between SUR1 and Kir6.2 or altered function of Kir6.2.
We have reported recently that cibenzoline, a class Ia antiarrhythmic
agent (11, 15, 18), blocks the
KATP channel activity in
pancreatic -cells and enhances insulin release by binding to a site
distinct from the glibenclamide binding site in SUR1 (17). In the
present binding study using SUR1- or Kir6.2-expressed cell membranes,
it was assumed that glibenclamide binds only to SUR1 and that
cibenzoline binds directly to Kir6.2 and not to SUR1, although it also
binds to other endogenous proteins expressed in wild type COS1 cells.
In addition, the inhibition of
KATP channel activity by
cibenzoline was not affected in the cell-attached configuration under
intracellular metabolic inhibition and at even lower intracellular ATP
concentrations in the inside-out configuration. These findings indicate
that the efficacy of cibenzoline on
KATP channel inhibition is not
affected by metabolic inhibition, including decreased ATP. It
seems likely, therefore, that the impaired closure of the
KATP channel is due to functional
impairment of signal transmission between SUR1 and Kir6.2.
The molecular mechanism of the reduced efficacy of glibenclamide on channel inhibition under metabolic stress is yet unclear but deserves consideration. SUR1 is a member of the ATP-binding cassette superfamily and possesses two nucleotide binding domains (1). From a reconstitution study of KATP channels by coexpression of SUR1 and Kir6.2 proteins, it was inferred that Kir6.2 acts as the pore-forming unit in KATP channels and that SUR1 confers the adenine nucleotide sensitivity required for modulation of KATP channel activity (16). A recent study, however, indicates that the primary site at which ATP acts to mediate KATP channel inhibition is located on Kir6.2 and that SUR1 enhances the ATP sensitivity of Kir6.2 (29). Our results also show that the dissociation constant and Hill coefficient of the dose-response curve were altered with decreased KATP channel inhibition by glibenclamide. Accordingly, it seems likely that altered binding status or hydrolysis of adenine nucleotides induces conformational changes of SUR1 or Kir6.2 (10), which could impair signal transmission between SUR1 and Kir6.2.
It has been thought that not only ATP but also MgADP [the ATP-to-ADP
ratio (ATP/ADP)] are important in the regulation of
KATP channels (19, 23). Recent
studies show that the potentiatory site of MgADP for channel activity
is in SUR1 (13, 25). In the present results, ATP/ADP seems to alter
under metabolic inhibition because of the increase of MgADP
concentration (7), and changes of ATP/ADP and MgADP itself might affect
KATP channel inhibition by
sulfonylurea mediation of SUR1 (31). The altered dose responsiveness of
glibenclamide on KATP channel
inhibition under metabolic inhibition might be explained by changes of
ATP/ADP or MgADP in the juxtamembranous space in pancreatic -cells.
On the other hand, the change of intracellular pH derived from
metabolic inhibition also could affect the regulation of
KATP channel activity in
-cells
(24, 26). Further examination is needed to clarify the details of the mechanism of this phenomenon.
Sulfonylureas have been used for more than 30 years in the treatment of
NIDDM patients. However, it has been observed in a considerable number
of patients that the hypoglycemic efficacy becomes reduced with poor
glycemic control. In some cases, the insulin secretory capacity has
been shown to be reduced (14). Regarding the pathogenesis of the
decrease in glucose-induced insulin secretion in NIDDM, we and others
have demonstrated an impaired intracellular glucose metabolism in
pancreatic -cells (12, 27). The pathogenesis of the reduced efficacy
of sulfonylureas in poorly controlled NIDDM, accordingly, might be a
defect in signal transmission between SUR1 and Kir6.2 occurring under
deteriorated glucose metabolism in pancreatic
-cells in diabetic
conditions. Clarifying the conformational interrelationships between
SUR1 and Kir6.2 that are required for mutual signal transmission should aid development of new agents that can act more directly on the Kir6.2
protein to inhibit channel activity and enhance insulin release in
NIDDM patients with sulfonylurea failure.
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ACKNOWLEDGEMENTS |
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The authors are grateful to Dr. N. Inagaki (Div. of Molecular Medicine, Center for Biomedical Science, Chiba University School of Medicine, Chiba, Japan) for donating COS1 cells expressing SUR1 or Kir6.2.
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FOOTNOTES |
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This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Culture of Japan; by the Committee of Experimental Models of Intractable Diseases of the Ministry of Health and Welfare of Japan; by a grant provided by the Japan Diabetes Foundation; and by a grant from the "Research for the Future" Program of the Japan Society for the Promotion of Science (JSPS-RFTF97100201).
Address for reprint requests: E. Mukai, Dept. of Metabolism and Clinical Nutrition, Faculty of Medicine, Kyoto Univ., 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606, Japan.
Received 15 May 1997; accepted in final form 18 September 1997.
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