2001 Fiscal Year Final Research Report Summary
Studies on multimolecular modulation of ATP-sensitive K^+ channels in pancreatic β-cells
| Project/Area Number |
12671119
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Akita University (2001)
Kagoshima University (2000) |
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Principal Investigator |
KAKEI Masafumi Akita University School of Medicine, Associate Professor, 医学部, 助教授 (90214270)
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| Co-Investigator(Kenkyū-buntansha) |
ITO Seiki Akita University School of Medicine, Professor, 医学部, 教授 (40126389)
NAKATA Masanori Jichi Medical College, School of Medicine, Lecturer, 医学部, 講師 (10305120)
YADA Toshihiko Jichi Medical College, School of Medicine, Professor, 医学部, 教授 (60166527)
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| Project Period (FY) |
2000 – 2001
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| Keywords | insulin secretion / K-ATP channels / sulfonylureas / membrane phospholipid / β-cells / actin / ATP / diabetes mellitus |
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| Research Abstract |
ATP-sensitive K^+ channels are composed of heteromultimers of sulfonylurea-receptor unit and pore unit of inwardly rectifying K^+ channels. Intracellular Ca^<2+> was found to inhibit functional transduction between binding of sulfonylureas to their receptors and closure of channels. Inhibition of intracellular metabolism by oxygen-free radicals resulted in a reduction of inhibitory efficacy of channels by sulfonylureas. Intracellular ATP was also one of modulators of signal transduction between these subunits, but was required to be decreased to concentrations <10 μM for inhibition of sulfonylurea-induced closure of the channel. Actin, cytoskeletal proteins, maintained the inhibitory effect of sulfonylureas on the channel, and PIP_2, plasma membrane phospholipids, stabilizes the actin effect by antagonizing intracellular Ca^<2+> that is reported to depolymerize actin filaments from F-actin to G-actin. PBP_2 also increased activity of the channel by reducing ATP sensitivity. Furthermore, we found that stimulation of P2Y-receptors by extracellularly applied ATP resulted in reduction of activity of cardiac ATP-sensitive K^+ channels via reduction of membrane PIP_2 levels. These results suggest that levels of membrane PIP_2 may be a determinant of basal activity of the channels. We propose that the channel is modulated by surrounding molecules: membrane phospholipids, Ca^<2+>, actin filaments and ATP.
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[Publications] Nakazaki, M., Kakei, M., Ishihara, H., Koriyama, N., Hashiguchi. H., Aso, K., Fukudome, M., Oka, Y., Yada, T., Tei, C: "Association of up-regulated activity of K_<ATP> channels with impaired insulin secretion in UCP1-expressing MIN6 cells"J.Physiology. (in press). (2002)
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[Publications] Oketani, N., Kakei, M., Ichinari, K., Okamura, M., Miyamura, M., Nakazaki, M., Ito, S., and Tei, T: "Regulation of ATP-sensitive K^+ channels by P2Y-purinoceptors coupled to PIP_2 metabolism in guinea-pig ventricular cells"Am J Physiol. 282. H757-H765 (2002)
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[Publications] Koriyama, N., Kakei, M., Nakazaki, M., Yaekura, K., Hashiguchi, H., Aso, K., Fukudome, M., Yada, T., Ito, S., and Tei, C.: "Free radical-mediated tolbutamide desensitization or K^+ATP channels in rat pancreatic β-cells"Endocrine Journal. 48. 337-344 (2001)
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[Publications] Okamura, M., Kakei, M., Ichinari, K., Miyamura, A., Oketani, N., Koriyama, N., and Tei, C.: "State-dependent modification of ATP-sensitive K^+ channels by phosphatidylinositol 4,5-bisphosphate"Am J Physiol. 280. C303-308 (2001)
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[Publications] Gong, Q., Kakei, M., Koriyama, N., Nakazaki, N., Morimitsu, S., Yaekura, K., and Tei, C.: "P2Y-purinoceptor mediated inhibition of L-type Ca^<2+> channels in rat pancreatic β-cells"Cell Struc. Func.. 25. 279-89 (2000)
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[Publications] Nakazaki, M., Kakei, M., Yaekura, K., Koriyama, N., Morimitsu, S., Ichinari, K., Yada,T. and Tei, C.: "Diverse effects of hydrogen peroxide on eytosolie Ca^<2+> homeostasis in rat pancreatic β-cells"Cell Struc Funct. 25. 187-193 (2000)
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[Publications] Koriyama, N., Kakei, M., Nakazaki, M., Yaekura, K., Ichinari, K., Yada, T, and Tei, C.: "PIP_2 and ATP cooperatively prevent cytosolic Ca^<2+>-induced modification of ATP-sensitive K^+ channels in rat pancreatic β-cells"Diabetes. 49. 1830-1839 (2000)
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[Publications] Miyamura, A., Kakei, M., Ichinari, K., Okamura, M., Oketani, N., and Tei, C.: "On the mechanism of ADP-induced alteration of sulfonylurea sensitivity in cardiac ATP-sensitive K^+ channels"Br J Pharmacol. 130. 1411-1417 (2000)
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