2000 Fiscal Year Final Research Report Summary
Upregulation of cardiac A_1 receptors their coupling to ATP-sensitive potassium channels.
| Project/Area Number |
11670051
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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 |
General physiology
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| Research Institution | Nihon University |
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Principal Investigator |
KOKUBUN Shinichiro Nihon university School of Medicine, Professor, 医学部, 教授 (20153520)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAO Kyoichi Nihon University School of Medicine, Assistant, 医学部, 助手 (90187922)
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| Project Period (FY) |
1999 – 2000
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| Keywords | cardiac ischemia / adenosine A_1-receptors / ATP-sensitive potassium channels / intracellular Ca^<2+> concentration / preconditioning / preconditioning |
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| Research Abstract |
Various studies suggest the contribution of adenosine A_1-receptors and ATP-sensitive potassium channels (K_<ATP> channels) as the physiological mechanisms protecting cardiac functions in ischemia. How they contribute to the protective action on cardiac myocytes, however, has not been elucidated yet. The most plausible working hypothesis is that the number of A_1-receptors immediately increases in response to ischemia, resulting in the decrease in intracellular cyclic AMP level which prevents the increase in intracellular Ca^<2+> concentration, and that K_<ATP> channels coupled to A_1-receptors are activated, resulting in the avoidance of excess depolarization of cardiac myocytes. In this study, to prove the hypothesis we tried to elucidate the following two points ; 1) A_1-recceptors rapidly increases in response to cardiac ischemia, 2)A_1-receptors are coupled to K_<ATP> channels by a mole-to-mole interaction. In rat heart the expression of A_1-receptor mRNA increased as twice as the control by the reperfusion for 10 min after ischemia with the period of 5 min. This effect was significantly enhanced by introducing preconditioning of 2 min, 5 min before ischemia. These results suggested that A_1-recptors rapidly increased in response to ischemia. We performed coexperssion of Kir_<6.2> and SUR_<2a> as the functional model of cardiac K_<ATP> channels, and we elucidate amino acid sequence of G-protein binding site of the channel. We also tried to coexpress A_1-receptors and K_<ATP> channels in order to examine the interaction between the receptor and the channel. Unfortunately, however, we could not record any channel activity from the cells in which these two proteins were supposed to be expressed. Further study is required to elucidate the mole-to-mole interaction between A_1-receptors and K_<ATP> channels.
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[Publications] Yoshiyuki Wada, Toshikazu Yamashita, Kohbun Imai, Reiko Miura, Kyoichi Takao, Miyuki Nishi, Hiroshi Takeshima, Tomiko Asano, Rika Morishita, Kazuhisa Nishizawa, Shinichiro Kokubun and Toshihide Nukada: "A region of the sulfonylurea receptor critical for a modulation of ATP-sensitive K^+ channels by G-protein βγ-subunits"The EMBO Journal. 19-18. 4915-4925 (2000)
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