2000 Fiscal Year Final Research Report Summary
Regulation of cardio-vascular ATP-sensitive K channels.
| Project/Area Number |
11694273
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| Research Category |
Grant-in-Aid for Scientific Research (A).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General pharmacology
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| Research Institution | Osaka University |
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Principal Investigator |
KURACHI Yoshihisa Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (30142011)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Masaru Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (10324758)
TANEMOTO Masayuki Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (40303945)
INANOBE Atsushi Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (00270851)
FUJITA Akikazu Osaka University Graduate School of Medicine, Assistant Professor, 農学部, 助手 (60282232)
MORISHIGE Ken-ichiro Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (90283788)
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| Project Period (FY) |
1999 – 2000
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| Keywords | Inwardly rectifying potassium channel / ATP-sensitive potassium channel / Sulfonylurea receptor / Potassium channel Opener / Cardio-vascular system |
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| Research Abstract |
(1) The ATP-sensitive K^+ (K_<ATP>) channels are composed of the pore-forming K^+ channel Kir6.0 and different sulfonylurea receptors (SURs). Although Kir6.1 and Kir6.2 are highly homologous, their unitary conductances are different. We found that a chain of three amino acid residues in the M1-H5 extracellular link and single residues in the H5-M2 link account for the difference. By using a 3D-structure model of Kir6.2, it was suggested that two independent plausible mechanisms are involved in the determination of single-channel conductance of the Kir6.0 subunits.
(2) The effects of a novel vasorelaxant agent, MCC-134 were examined on reconstituted K_<ATP> channels containing Kir6.2 and either SUR1, SUR2A or SUR2B.MCC-134 activated the SUR2B/Kir6.2 channel, was a weak activator of the SUR2A/Kir6.2 channel, but suppressed SUR1/Kir6.2 channel. Thus, it was revealed that MCC-134, which is a relatively effective opener of the vascular smooth muscle-type K_<ATP> channel, is an antagonist of the pancreatic-type K_<ATP> channel.
(3) We revealed that the C-terminal tail of SURs plays a critical role in the differential activation of different SUR-K_<ATP> channels by ADP and diazoxide. In the present study, much higher concentrations of ADP were needed to activate channels that contained SUR2A than SUR1 or SUR2B.In all types of K_<ATP> channels, diazoxide increased potency but not efficacy of ADP to evoke channel activation. Replacement of the C-terminal segment of SUR1 with that of SUR2A inhibited ADP-mediated channel activation and reduced diazoxide modulation. Point mutations of the second nucleotide-binding domains (NBD2) of SUR1 and SUR2B showed similar effects. Therefore, it was suggested that the C-terminal segment of SUR2A possesses an inhibitory effect on NBD2-mediated ADP-induced channel activation, which underlies the differential effects of ADP and diazoxide on K_<ATP> channels containing different SURs.
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