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Studies on multimolecular modulation of ATP-sensitive K^+ channels in pancreatic β-cells

Research Project

Project/Area Number 12671119
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionAkita University (2001)
Kagoshima University (2000)

Principal Investigator

KAKEI Masafumi  Akita University School of Medicine, Associate Professor, 医学部, 助教授 (90214270)

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)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2000: ¥2,600,000 (Direct Cost: ¥2,600,000)
Keywordsinsulin secretion / K-ATP channels / sulfonylureas / membrane phospholipid / β-cells / actin / ATP / diabetes mellitus / ATP感受性K^+チャネル / 膵β細胞 / PIP2 / 細胞骨格
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.

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (39 results)

All Other

All Publications (39 results)

  • [Publications] Nakazaki, M.: "Association of up-regulated activity of K_<ATP> channels with impaired insulin secretion in UCP 1-expressing MIN6 cells"J. Physiology. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujita, H.: "Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance"Renal Failure. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Narita, T.: "Aggressive antihypertensive treatment and serum lipid lowering therapy are necessary to prevent deterioration of renal function even in elderly type 2 diabetic patients with persistent albuminuria"Gerontology. (in press). (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Oketani, N.: "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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Koriyama, N.: "Free radical-mediated tolbutamide desensitization of K^+ATP channels in rat pancreatic β-cells"Endocrine Journal. 48. 337-344 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Okamura, M.: "State-dependent modification of ATP-sensitive K^+ channels by phosphatidylinositol 4,5-bisphosphate"Am J Physiol. 280. C303-C308 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Gong, Q: "P2Y-purinoceptor mediated inhibition of L-type Ca^<2+> channels in rat pancreatic β-cells"Cell Struc Func. 25. 279-289 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakazaki, M.: "Diverse effects of hydrogen peroxide on cytosolic Ca^<2+> homeostasis in rat pancreatic β-cells"Cell Struc Func. 25. 187-193 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Koriyama, N.: "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)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miyamura, A.: "On the mechanism of ADP-induced alteration of sulfonylurea sensitivity in cardiac ATP-sensitive K^+ channels"Br J Pharmacol. 130. 1411-1417 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 加計正文: "Annual Review 内分泌・代謝、インスリン分泌の分子機構"中外医学社. 294 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Fujita H. Narita T. Morii T. Shimotomai T. Yoshioka N. Kakei M. Ito S.: "Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance"Renal Failure. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Narita T. Kakei M. Ito S.: "Aggressive antihypertensive treatment and serum lipid lowering therapy are necessary to prevent deterioration of renal function even in elderly type 2 diabetic patients with persistent albuminuria"Gerontology. (in press). (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [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)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Kakei, M, Nakata, M, and Yada, T: "Annual Review Endocrine and Meabolism: Molecular mechanism of insulin secretion"Chugai Igakusha. 294 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Nakazaki, M.: "Association of up-regulated activity of K^<ATP> channels with impaired insulin secretion in UCP1-expressing MIN6 cells"J.Physiol. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fujita, H.: "Increased urinary excretion of N-acetylglucosaminidase in subjects with impaired glucose tolerance"Renal Failure. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Narita, T.: "Aggressive antihypertensive treatment and serum lipid lowering therapy are necessary to prevent deterioration of renal function even in elderly type 2 diabetic patients with persistent albuminuria"Gerontology. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Oketani, N.: "Regulation of ATP-sensitive K^+ channels by P2Y-purinoceptors coupled to PIP_2 metabolism in guinea-pig ventricular cells"Am J Physiol. 282・2. H757-H765 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Koriyama, N.: "Free radical-mediated tolbutamide desensitization of K^+ATP channels in rat pancreatic β-cells"Endocrine Journal. 48・3. 337-344 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okamura, M.: "State-dependent modification of ATP-sensitive K^+ channels by phosphatidylinositol 4,5-bisphosphate"Am J Physiol. 280・2. C303-C308 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Gong, Q.: "P2Y-purinoceptor mediated inhibition of L-type Ca^<2+> channels in rat pancreatic β-cells"Cell Struc Func. 25・5. 279-289 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakazaki, M.: "Diverse effects of hydrogen peroxide on cytosolic Ca^<2+> homeostasis in rat pancreatic β-cells"Cell Struc Func. 25・3. 187-193 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Koriyama, N.: "PIP_2 and ATP cooperatively prevent cytosolic Ca^<2+>-induced modification of ATP-sensitive K^+ channels in rat pancreatic β-cells"Diabetes. 49・11. 1830-1839 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miyamura, A.: "On the mechanism of ADP-induced alteration of sulfonylurea sensitivity in cardiac ATP-sensitive K^+ channels"Br J Pharmacol. 130・6. 1411-1417 (2000)

    • Related Report
      2001 Annual Research Report
  • [Publications] 加計正文: "Annual Review 内分泌・代謝、インスリン分泌の分子機構"中外医学杜. 294 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Okamura M,Kakei M,Ichinari K,Miyamura A,Oketani N,Koriyama N,Tei C: "State-dependent modification of ATP-sensitive K^+ channels by phosphatidylinositol 4,5-bisphosphate"Am J Physiol.(Cell Physiol). 280. C303-C308 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Gong Q,Kake Mi,Koriyama N,Nakazaki M,Morimitsu S,Yaekura K,Tei C: "P2Y-Purinoceptor Mediated Inhibition of L-type Ca^<2+> Channels in Rat Pancreatic β-Cells."Cell Structure and Function. 25. 279-289 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Nakazaki M,Kakei M,Yaekura K,Koriyama N,Morimitsu S,Ichinari K,Yada T,and Tei C: "Diverse effects of hydrogen peroxide on cytosolic Ca^<2+> homeostasis in rat pancreatic β-cells,"Cell Structure and Function. 25. 187-193 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koriyama N,Kakei M,Nakazaki M,Yaekura K,Ichinari K,Yada T.and Tei C: "PIP2 and ATP cooperatively prevent cytosolic Ca^<2+>-induced modification of ATP-sensitive K^+ channels in rat pancreatic β-cells"Diabetes. 49. 1830-1839 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Koriyama N,Kakei M,Yaekura K Okui H,Yamashita T,Nishimura H,Matsushita S and Tei C: "Pheochromocytoma of which catecholamine release and blood pressure were controlled by somatostatin : a case with an in vitro study"Hormone Research. 53. 46-50 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miyamura A,Kakei M,Ichinari K,Okamura M,Oketani N and Tei C: "On the mechanism of ADP-induced alteration of sufonylurea sensitivity in cardiac ATP-sensitive K^+ channels"British Journal of Pharmacology. 130. 1411-1417 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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