Development of drugs which open or close ATP-sensitive KィイD1+ィエD1channels

开发打开或关闭 ATP 敏感 KiiD1+iED1 通道的药物

• 批准号: 10557002
• 负责人: INAGAKI Nobuya
• 金额: $ 7.1万
• 依托单位: AKITA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557002/
• 关键词: sulfonylurea; chimera; G-protein; thiazolidinedione; ATP-sensitive KィイD1+ィエD1channel; substania nigra; knockout mouse; ischemia; 神経細胞; 黒質網様部; ATP感受性K^+チャネル; インスリン; スルホニル尿素; 膵β細胞; 心筋細胞

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 … More 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

ATP敏感的Ky D1+IE D1（Ky D2ATPIE D2）通道是关键分子，将细胞的代谢状态与其膜电位联系起来。我们已经确定胰腺β-cell ky d2atpie D2通道包括内向整流器Kir6.2和磺酰脲受体SUR1亚基，而心脏KY D2ATPIE D2通道包括Kir6.2和Sur2a，Sur2a是SUR1的同工型。我们在这项研究中的目的是开发专门打开或关闭这些渠道的药物。我们的结果如下。＃我们已经确定了将KYI D2ATPIE D2通道对磺酰尿素和KYI D2ATPIE D2频道开启的二氧氧化物的敏感性的区域，通过分析SUR1和SUR2之间的一系列Chimeras，我们已经在Sur1和Sur2之间进行了一系列chimeras。我们已经表明，G蛋白α亚基直接调节KYI D2ATPIE D2通道活性，并且在β细胞和心脏KYI D2ATPIE D2通道之间的调控是不同的，这表明D…更多的基础架构是由众所周知的niacorived sorivient of the Innin serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivient serivine sor的效应的调节。 KYI D2ATPIE D2频道。 troglitazone以剂量依赖性方式抑制β细胞和心脏Kyi D2ATPIE D2通道；它以30-100μm抑制前者，并在3μm下抑制后期。这表明troglitazone调节了各种细胞功能，包括胰岛素分泌和肌肉收缩，尤其是在缺血状态下。我们已经研究了来自底本底虫（Nigra pars）网状（SNR）的急性解离神经元中KYI D2ATPIE D2通道活性的电生理特性。该通道的药物特性与β细胞KYI D2ATPIE D2通道的药物相似。 Kyi D2ATPIE D2通道淘汰小鼠是通过靶向Kir6.2基因（在Chiba University的Seino实验室成立的）而产生的，其中Kyi D2ATPIE D2 Channel活动在SNR中不存在，很容易受到iSchemia的影响，表明Kyi D2atpie D2Atpie D2频道在反对Ischepic中起着重要的作用。

项目成果

Nakata, M. and Inagaki, N.: "Molecular mechanism of insulin recretion."Mebio. 15. 24-29 (1998)

Nakata, M. 和 Inagaki, N.：“胰岛素分泌的分子机制”。Mebio。

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)

Yamada K.、Nakata M.、Horimoto N.、Saito M.、Matuoka H. 和 Inagaki N.：“单个活胰腺 β 细胞中葡萄糖摄取和细胞内钙浓度的测量”J. 2000)

Sanchez, J.A., Gonoi, I., Inagaki, N., Katada, T., and Seino, S.: "Modulation of reconstituted ATP-sensitive K^+ channels by GTP-binding proteins." J.Physiol.507. 315-324 (1998)

Sanchez, J.A.、Gonoi, I.、Inagaki, N.、Katada, T. 和 Seino, S.：“GTP 结合蛋白对重建 ATP 敏感 K^ 通道的调节”。

Sunaga, Y., Inagaki, N., et al.: "Troglitazone but not pioglitazone affects ATP-sensitive KィイD1+ィエD1 channel activity."Eur. J. Pharmacol.. 381. 71-76 (1999)

Sunaga, Y., Inagaki, N. 等人：“曲格列酮影响 ATP 敏感的 KiD1+KiD1 通道活性。”Eur. J. Pharmacol.. 381. 71-76 (1999)

Inagaki, N.: "Molecular structure and function of KィイD2ATPィエD2 channels."Jin to Touseki. 45. 651-656 (1998)

Inagaki, N.：“KIID2ATPIED2 通道的分子结构和功能。”Jin to Touseki，45. 651-656 (1998)