Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic beta -cells

Eri Mukai1, Hitoshi Ishida1, Seika Kato1, Yoshiyuki Tsuura1, Shimpei Fujimoto1, Ayako Ishida-Takahashi2, Minoru Horie2, Kinsuke Tsuda3, and Yutaka Seino1

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

    ABSTRACT
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Abstract
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Methods
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Discussion
References

The effect of metabolic inhibition on the blocking of beta -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 beta -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

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

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 beta -cells (3).

Closure of the KATP channels plays a key role in the insulin secretory mechanism of pancreatic beta -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 beta -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 beta -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 beta -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 beta -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.

    METHODS
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Introduction
Methods
Results
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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 MOmega ) 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(beta -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).

Current data were recorded through a patch-clamp amplifier (EPC-9; HEKA Elektronik, Lambrecht, Germany) and stored on videotape via a pulse code modulation converting system (VR-10B; Instrutech, NY), and off-line analysis was performed on the pCLAMP6 program (Axon Instruments, Foster City, CA) at the sampling rate of 1 kHz. The patches were challenged sequentially by each test solution for 2 min, and open probability (Po) of channels was determined by the current during the last 30-s interval of each challenge. The relative channel activity was expressed as Po/Poc, where Poc is the open probability of channels in the control solution. Po/Poc was fitted to the Hill equation
<IT>P</IT><SUB>o</SUB> /<IT>P</IT><SUB>oc</SUB> = [1 + ([X]/IC<SUB>50</SUB>)<SUP><IT>n</IT></SUP>]<SUP>−1</SUP>
where [X] is the concentration of glibenclamide or cibenzoline, IC50 is the half-maximal concentration for inhibition of these materials, and n is the Hill coefficient.

[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.

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

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 beta -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 beta -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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Fig. 1.   Effect of 2,4-dinitrophenol (DNP) on ATP-sensitive K+ channel (KATP channel) inhibition by glibenclamide. The traces are recorded at 0 mM pipette potential in the cell-attached configuration. A: representative channel current trace in the presence of various concentrations of glibenclamide. Upward current of channel recording shows inward channel current. B: representative channel current trace in the presence of various concentrations of glibenclamide under DNP. C: dose-response curves of KATP channel inhibition by glibenclamide in the absence or presence of DNP. Relative channel activities in the absence (open circle ) and in the presence of DNP (bullet ) are plotted against various concentrations of glibenclamide (n = 5-12).

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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Fig. 2.   Comparison of KATP channel inhibition by glibenclamide in 10 and 0.1 µM ATP. Traces are recorded at -70 mV pipette potential in inside-out configuration. A: representative channel current trace in the presence of various concentrations of glibenclamide under 10 µM ATP. Upward current of channel recording indicates inward channel current. B: representative channel current trace in the presence of various concentrations of glibenclamide under 0.1 µM ATP. C: dose-response curves of KATP channel inhibition by glibenclamide in 10 and 0.1 µM ATP. Relative channel activities in 10 µM ATP (open circle ) and 0.1 µM ATP (bullet ) are plotted against various concentrations of glibenclamide (n = 5-10). D: direct effect of DNP on KATP channel activity.

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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Fig. 3.   Effect of DNP on displacement of specific [3H]glibenclamide binding by nonradioactive glibenclamide in pancreatic islet cells. Bindings of [3H]glibenclamide after 30-min incubations in the absence (open circle ) and presence (bullet ) of DNP were similarly displaced by nonradioactive glibenclamide (n = 5).

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 beta -cells (5). Recently, Kakei et al. (19) and we (17) both reported that cibenzoline blocks KATP channels in pancreatic beta -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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Fig. 4.   Effect of DNP on KATP channel inhibition by cibenzoline. Traces are recorded at 0 mM pipette potential in cell-attached configuration. A: representative channel current trace in the presence of various concentrations of cibenzoline. Upward current of channel recording shows inward channel current. B: representative channel current trace in the presence of various concentrations of cibenzoline under DNP. C: dose-response curves of KATP channel inhibition by cibenzoline in the absence or presence of DNP. Relative channel activities in the absence of DNP (open circle ) and in the presence of DNP (bullet ) are plotted against various concentrations of cibenzoline (n = 5-11).

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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Fig. 5.   Comparison of KATP channel inhibition by cibenzoline in 10 and 0.1 µM ATP. Traces are recorded at -70 mV pipette potential in inside-out configuration. A: representative channel current trace in the presence of various concentrations of cibenzoline under 10 µM ATP. Upward current of channel recording indicates inward channel current. B: representative channel current trace in the presence of various concentrations of cibenzoline under 0.1 µM ATP. C: dose-response curves of KATP channel inhibition by cibenzoline in 10 and 0.1 µM ATP. Relative channel activities in 10 µM ATP (open circle ) and 0.1 µM ATP (bullet ) are plotted against various concentrations of cibenzoline (n = 5-11).

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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Fig. 6.   Comparison of [3H]glibenclamide (A) and [3H]cibenzoline (B) specific binding to sulfonylurea receptor in pancreatic beta -cells (SUR1) or the inward rectifier K+ channel (Kir6.2) proteins expressed in COS1 cells. * Significant differences: P < 0.01.

    DISCUSSION
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Abstract
Introduction
Methods
Results
Discussion
References

The present study shows that beta -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 beta -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 beta -cells. On the other hand, the change of intracellular pH derived from metabolic inhibition also could affect the regulation of KATP channel activity in beta -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 beta -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 beta -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.

    ACKNOWLEDGEMENTS

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.

    FOOTNOTES

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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Abstract
Introduction
Methods
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Discussion
References

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AJP Endocrinol Metab 274(1):E38-E44
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