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1993 Fiscal Year Final Research Report Summary

Molecular Anatomy of Cardiac Ion Channels by Developing and Applying New Molecular Tools

Research Project

Project/Area Number 04671279
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Chemical pharmacy
Research InstitutionKumamoto University (1993)
Hokkaido University (1992)

Principal Investigator

NAKAYAMA Hitoshi  Kumamoto University, Faculty of Pharmaceutical Science, Professor, 薬学部, 教授 (70088863)

Co-Investigator(Kenkyū-buntansha) KUNIYASU Akihiko  Hokkaido University, Faculty of Pharmaceutical Sciences Instructor, 薬学部, 助手 (90241348)
YOSHII Kiyonori  Kyushu Institute of Technology, Faculty of Industry, Associate Professor, 工学部, 助教授 (30125364)
HATANAKA Yasumaru  Toyama Medical Pharmaceutical College, Institute of Wakan-Yaku, Associate Profes, 薬学部, 助手 (30111181)
Project Period (FY) 1992 – 1993
KeywordsCardiac Ca^<2+>channel / Dihydropyridine reagent / Drug binding sites / ATP-sensitive K^+channel / Candidate protein / Anti-arrhythmic analog / Photoaffinity labeling
Research Abstract

Cardiovascular diseases are serious problems in health ranking the highest lethal rate in modern society. In order to diagonize the patients, reveal their causes, and establish better therapeutic methods, it is essential to reveal structures and functions of molecules that are relevant to cardiac excitation and propagation. We investigated three cardiac channels (Ca^<2+>channel, Na^+channel, and ATP-sensitive K^+channel) by various methods including chemical, biochemical, immunochemical, and electrophysiological techniques. The results obtained after 2 years works are summarized as follows.
(1) We are succeeded in identifying the binding sites of a typical calcium antagonist (dihydropyridine) in Ca^<2+>channel by photoaffinity labeling with a newly synthesized reagent. The sites revealed were identical to the skeletal muscle counterpart, but several substitution in amino acids was observed in the sites. They may imply the 10-fold difference of binding affinity between the two channels.
(2) A potential candidate protein of ATP-sensitive K^+channel was isolated by biochemical purification of the cardiac preparations that were photolabeled with a new glibenclamide derivative. Immunohisto-chemical experiments showed that the protein was localized in the membrane surface of the ardiac venticules.
(3) Mexiletine analogs for photoaffinity labeling and antibody generation were synthesized as molecular probes of a typical class I anti-arrhythmic agent for cardiac Na^+channels.

  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Nakayama,H.: "Photolabeled Sites with a Tetrodotoxin Derivative in the Domain III and IV of the Electroplax Sodium Channel." Biochem.Biophys.Res.Commun..184. 900-907 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Hatanaka,Y.: "Photoaffinity Labeling of the Electroplax Sodium Channel with a Photoreactive μ-Conotoxin Carring a Radioactive and Chromogenic Derivative." Chem Pharm.Bull.40. 2537-2539 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kuniyasu,A.: "Structural Characterization of the Cardiac Calcium Channel from Porcine Hearts." J.Biochem.112. 235-242 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakayama,H.: "Characterization of Saccharide Moiety in the Electroplax Sodium Channel." Chem.Pharm.Bull.40. 3287-3291 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakayama,H.: "A Site-Directed Antibody Which Inhibits Phosphorylation of the Rat Brain Sodium Channel by cAMP-depemdent Protein Kinase." Biochim.Biophys.Acta. 1175. 67-72 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakayama,H.: "A Topographical Study of the Electroplax Sodium Channel with Site-Directed Antibodies" Biochim.Biophys.Acta. 1145. 134-140 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakayama,H.: "Methods in Pharmacology,vol.7(eds.H.Glossmann,J.Striessnig)" Plenum Press(New York), 280 (1993)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 中山 仁: "生体膜工学(Maruzen Advanced Technologyシリーズ,第7巻、二井将光・編)6章“イオンチャンネル構造とイオン輸送機構"" 丸善, 330 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Nakayama, H., Hatanaka, Y., Yoshida, E., Oka, K., Takanohashi, M., Amano, Y,. Kanaoka, Y.: "Photolabeled Sites with a Tetrodotoxin Derivative in the Domain III and IV of the Electroplax Sodium Channel." Biochem.Biophys.Res.Commun.184. 900-907 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Hatanaka, Y., Nakayama, H., Kanaoka, Y.: "Photoaffinity Labeling of the Electroplax Sodium Channel with a Photoreactive mu-Conotoxin Carring a Radioactive and Chromogenic Derivative." Chem Pharm.Bull.40. 2537-2539 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kuniyasu, A., Oka, K., Ide-Yamada, T., Hatanaka, Y., Abe, T., Nakayama, H., Kanaoka, Y.: "Structural Characterization of the Cardiac Calcium Channel from Porcine Hearts." J.Biochem.112. 235-242 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakayama, H., Yamamoto, S., Hatanaka, Y., Hachisu, T., Tsunasawa, S., Sakiyama, F., Kanaoka, Y.: "Characterization of Saccharide Moiety in the Electroplax Sodium Channel." Chem.Pharm.Bull.40. 3287-3291 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakayama, H., Shikano, H., Kanaoka, Y.: "A Site-Directed Antibody Which Inhibits Phosphorylation of the Rat Brain Sodium Channel by cAMP-dependent Protein Kinase." Biochim.Biophys.Acta. 1175. 67-72 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakayama, H., Nakayama, K., Nonomura, Y., Kobayashi, M., Kangawa, K., Matsuo, H., Kanaoka, Y.: "A Topographical Study of the Electroplax Sodium Channel with Site-Directed Antibodies." Biochim.Biophys.Acta. 1145. 134-140 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kalasz, H., Watanabe, T., Yabana, H., Itagaki, K., Naito, K., Nakayama, H., Schwartz, A., Vaghy, P.L.: "Identification of 1,4-Dihydropyridine Binding Domains within the Primary Structure of the alpha 1 Subunit of the Skeletal Muscle L-type Calcium Channel." FEBS Letters. 331. 177-181 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Watanabe, T., Kalasz, H., Yabana, H., Kuniyasu, A., Mershon, J., Itagaki, K., Vaghy, P.L., Naito, K., Nakayama, H., Schwartz, A.: "Azidobutyryl Clentiazem, A New Photoactivatable Diltiazem Analog, Labels Benzothiazepine Binding Sites in the al subunit of the Skeletal Muscle Calcium Channel." FEBS Letters. 334. 261-264 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakayama, H., Taki, M., Kanaoka, Y.: "Synthesis and Properties of Diazipine, A novel Photoaffinity Probe of Calcium Channel-Linked Dihydropyridine Receptors." Methods in Pharmacology. vol.7(eds.H.Glossmann, J.Striessnig), Plenum Press, (New York). 255-266 (1993)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1995-03-27  

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