1993 Fiscal Year Final Research Report Summary
Molecular Anatomy of Cardiac Ion Channels by Developing and Applying New Molecular Tools
| Project/Area Number |
04671279
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Chemical pharmacy
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| Research Institution | Kumamoto University (1993)
Hokkaido University (1992) |
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Principal Investigator |
NAKAYAMA Hitoshi Kumamoto University, Faculty of Pharmaceutical Science, Professor, 薬学部, 教授 (70088863)
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| 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)
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| Project Period (FY) |
1992 – 1993
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| Keywords | Cardiac Ca^<2+>channel / Dihydropyridine reagent / Drug binding sites / ATP-sensitive K^+channel / Candidate protein / Anti-arrhythmic analog / Photoaffinity labeling |
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| 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.
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[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)
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[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)
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[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)
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[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)
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[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)
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[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)
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