1999 Fiscal Year Final Research Report Summary
Development of drugs which open or close ATP-sensitive KィイD1+ィエD1channels
| Project/Area Number |
10557002
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
General physiology
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| Research Institution | AKITA UNIVERSITY |
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Principal Investigator |
INAGAKI Nobuya School of Medicine, Akita University, Professor, 医学部, 教授 (30241954)
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| Co-Investigator(Kenkyū-buntansha) |
OKADA Toshikazu Novartis Pharma Co. Ltd., Group Manager, 宝塚研究所, グループマネージャー研究職
FURUKAWA Tetsushi School of Medicine, Akita University, Associate Professor, 医学部, 助教授 (80251552)
YAMADA Katsuya School of Medicine, Akita University, Assistant, 医学部, 助手 (40241666)
HORIMOTO Naoki Graduate School of Medical Science, Kyusyu University, Faculty of Medicine, Assistant, 大学院・医学研究科, 助手 (40243927)
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| Project Period (FY) |
1998 – 1999
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| Keywords | sulfonylurea / chimera / G-protein / thiazolidinedione / ATP-sensitive KィイD1+ィエD1channel / substania nigra / knockout mouse / ischemia |
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| Research Abstract |
ATP-sensitive KィイD1+ィエD1(KィイD2ATPィエD2) channels are key molecules which link the cell's metabolic status to its membrane potential. We have determined that pancreatic β-cell KィイD2ATPィエD2 channel comprises the inward rectifier Kir6.2 and the sulfonylurea receptor SUR1 subunits, while the cardiac KィイD2ATPィエD2 channel comprises Kir6.2 and SUR2A, an isoform of SUR1. Our purpose in this study is to develop the drugs which open or close these channels specifically. Our results are as follows.
# We have determined the regions which confer the sensitivities of the KィイD2ATPィエD2 channels to the sulfonylurea and the KィイD2ATPィエD2 channel opener diazoxide, by analyzing a series of chimeras between SUR1 and SUR2.
# We have investigated the effects of G-protein on the reconstituted KィイD2ATPィエD2 channels. We have shown that G-protein α subunit directly regulates the KィイD2ATPィエD2 channel activity, and that the regulation is different between β-cell and cardiac KィイD2ATPィエD2 channels, suggesting that the d
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ifference is determined by distinct SUR subunits.
# We have investigated the effects of the thiazolidinedione derivatives, which are known to improve insulin resistance, on the reconstituted KィイD2ATPィエD2 channels. Troglitazone inhibited β-cell and cardiac KィイD2ATPィエD2 channels in a dose dependent manner; it inhibited the former at 30-100 μM and the late at 3 μM. This suggests that troglitazone modulates the various cellular functions including insulin secretion and muscle contraction especially under ischemic condition.
# It has been known that KィイD2ATPィエD2 channels are expressed in brain, and are especially abundant in substantial nigra. We have studied the electrophysiological properties of the KィイD2ATPィエD2 channel activity in the acutely dissociated neurons from substantia nigra pars reticulate (SNr). The pharmacological properties of the channel are similar to those of the β-cell KィイD2ATPィエD2 channel. KィイD2ATPィエD2 channel knockout mice generated by targeting the Kir6.2 gene (established in Professor Seino's lab in Chiba University), in which KィイD2ATPィエD2 channel activity is absent in SNr, are vulnerable to ischemia, suggesting that KィイD2ATPィエD2 channels play an important role in protection against an ischemic insult. Less
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Research Products
(24 results)
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[Publications] Yamada, K., Nakata, M., Horimoto, N., Saito, M., Matuoka, H. and Inagaki, N.: "Measurement of glucose uptake and intracellular calcium concentration in single, living pancreatic β-cells."J. Biol., Chem.. in press. (2000)
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