1998 Fiscal Year Final Research Report Summary
Elucidation of the mechanisms underlying the regulation of ATP-sensitive K^+ channels by sulfonylureas
| Project/Area Number |
09671025
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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 |
内分泌・代謝学
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| Research Institution | Akita University |
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Principal Investigator |
INAGAKI Nobuya Akita University, School of Medicine, Professor, 医学部, 教授 (30241954)
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| Project Period (FY) |
1997 – 1998
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| Keywords | sulfonylurea / ATP-sensitive K^* channel / inward rectifier K^* channel / knockout mouse / pancreatic beta-cell / ABC protein / cardiac myocyte |
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| Research Abstract |
ATP-sensitive K^+(K_<ATP>) channels are key molecules which link the cell's metabolic status to its membrane potential. In pancreatic beta-cells, KK_<ATP> channel is not only a glucose sensor m insulin secretion but also a target for the insulin secretagogue, the sulfonylurea, widely used as oral hypoglycemic agents in the treatment of diabetes mellitus. In cardiac myocytes and neurons, K_<ATP> channels are supposed to be involved in cytoprotection in ischemia, We have shown that beta-cell K_<ATP> channel is a complex of the sulfonylurea receptor SURI and a newly cloned inward rectifier K_<ATP> channel member Kir6.2, and that cardiac myocyte K_<ATP> channel is a complex of the newly cloned sulfonylurea receptor SUR2 and the Kir6.2. Our purpose in this study is to clarify the molecular mechanisms underlying the regulation of K^+ channels.
Sensitivities of the [3-cell (SUR1/Kir6.2) and cardiac (SUR2/Kir6.2) K_<ATP> channels to the sulfonylurea glibenclamide and the K_<ATP> channel opener
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diazoxide are different, and are determined by distinct SUR subunits. To determine the domains that confer glibenclamide and diazoxide sensitivities, we prepared a series of chimeras between SUR1 and SUR2, and studied the properties of the chimeric K_<ATP> channels. All chimeric SURs could generate currents when expressed in COS 1 cells with Kir6.2. Next, we have examined the effects of the glibenclamide and diazoxide on the chimeric currents measured as ^<86>Rb^+ efflux, and narrowed the region that confer the sensitivities to these reagents. Furthermore, we have constructed various chimeras between SUR1 and SUR2, and have almost determined the glibenclamide-responsive region by measuring the binding activities of @SH-labeled glibenclamide for the chimeras expressed in COS 1 cells (manuscript in 3@E1preparation).
In addition, we have investigated the effects of G-protein on the reconstituted K_<ATP> channels. We have shown that G-protein alpha subunit directly regulates the K_<ATP> channel activity, and that the regulation is different between [3-cell (SUR1/Kir6.2) and cardiac (SUR2/Kir6.2) K_<ATP> channels, suggesting that the difference is determined by distinct SUR subunits. Less
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