1996 Fiscal Year Final Research Report Summary
Study of intracellular modulation mechanisms of cardiac ATP-sensitive K^+ channels and their pathophysiological implications.
| Project/Area Number |
07457165
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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 | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
HIRAOKA Masayasu Tokyo Medical & Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (80014281)
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| Co-Investigator(Kenkyū-buntansha) |
HIRANO Yuji Tokyo Medical & Dental University, Medical Research Institute, Assistant Profess, 難治疾患研究所, 助手 (00181181)
SAWANOBORI Tohru Tokyo Medical & Dental University, Medical Research Institute, Associate Profess, 難治疾患研究所, 助教授 (00014217)
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| Project Period (FY) |
1995 – 1996
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| Keywords | ATP-sensitive K^+ channel / rundown of the channel activity / intracellular ATP / ADP / actin cytoskeleton / adenosine / protein kinase C |
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| Research Abstract |
The ATP-sensitive K^+ channels (K_<ATP>) are characterized by a strong inhibition by [ATP]_I but ATP is also necessary for the channels in an operative states. There are numerous factors to modulate the channel functions, which are difficult to attribute to real role for their openings during myocardial ischemia. We previously demonstrated that reactivation of after rundown by MgATP was caused by hydrolysis. Since ATP hydrolysis is also utilized in the process of actin cytoskeletal assembly, we examined the linkage between the K_<ATP> activity and the status of actin polymerization. Application of actin disrupters induced quick rundown. Actin stabilizers restored the channel activity in partially rundown channels, while they were ineffective in complete rundown or fully activated channels. MgATP plus F-actin restored the completely rundown channels. Therefore, the assembly and disassembly of actin cytoskeleton play a modulatory role for K_<ATP> Next, we examined whether or not K_<ATP>
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could be opened in the presence of milimor order of [ATP]_I. Using the trypsin-treated patches which showed least rundown, the presence of ADP plus Mg^<2+>, low pH increased the channel open probability in the presence of 1-2 mM [ATP]_I. From these results, we can conclude that K_<ATP> will be opened during early phase of myocardial ischemia where cellular ATP levels do not drop dramatically. This openings can be achieved with the presence of co-factors such as ADP and low pH,which are associated with ischemia. Another ischemic product, adenosine, is supposed to be an activator of K_<ATP> during myocardial ischemis, but its actual contribution in the whole-cell condition has not been demonstrated. We used a nystatin-perforated method which did not disturb the cellular condition. Using this technique, adenosine was shown to shorten K_<ATP> openings during metabolic inhibition, which was mediated through A2-receptor stimulation. The activation of PKC was also involved the K_<ATP> openings, but adenosine and PKC did not work synergistically as reported by the other groups. The intracellular mechanism between A2-receptor and PKC activation is under the extensive investigation. Less
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