Structure and physiological role of ATP-sensitive potassium channel

ATP敏感钾通道的结构和生理作用

• 批准号: 11470009
• 负责人: INAGAKI Nobuya
• 金额: $ 9.02万
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470009/
• 关键词: ATP-sensitive K^+ channel; pancreatic β -cell; insulin secretion; glucose; knockout mouse; substantia nigra; hypoxia; generalized seizures; 代謝ストレス; 神経細胞; 高山病; K_<ATP>チャネル; 虚血; 静止膜電位

ATP-sensitive K^+ (K_<ATP>) channels are key molecules which link the cell's metabolic status to its membrane potential. We have determined that pancreatic β -cell K_<ATP> channel comprises the inward rectifier Kir6.2 and the sulfonylurea receptor SUR1 subunits. Our results are as follows.# We have revealed by immunohistochmical study that SUR1 is expressed not only in pancreatic β -cells but also in glucagon-positive, somatostatin-positive, or pancreatic polypeptide-positive cells. Although the physiological role of the K_<ATP> channels in these cells is unknown, these results suggest that sulfonylureas may exert some effects on these cells through SUR1.# We have developed the method to measure both glucose transport and its effect on the various intracellular functions in single, living pancreatic β -cells, by using a fluorescent derivative of D-glucose, 2-NBDG. By using this novel method, we have revealed that glucose metabolism as well as glucose uptake is critical in glucoseinduced insulin secretion from pancreatic β -cells, verifying the importance of K_<ATP> channels in insulin secretion.# The substantia nigra pars reticulata (SNr), tjae area with the highest expression of K_<ATP> channels in the brain, plays a pivotal role in the control of seizures. We have shown that mutant mice lacking the Kir6.2 subunit of K_<ATP> channels (KO mice) are susceptible to generalized seizures after brief hypoxia. In normal mice, SNr neuron activity was inactivated during hypoxia by the opening of the post-synaptic K_<ATP> channels, while in KO mice the activity of these neurons was enhanced. These results suggest that K_<ATP> channels exert a depressant effect on SNr neuronal activity during hypoxia by an opening of the channels, and is involved in the nigral protection mechanism against generalized seizures.

ATP敏感的K^+（K_ <ATP>）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 k_ <ATP>通道包括内向整流器Kir6.2和磺基脲受体SUR1亚基。我们的结果如下。＃我们通过免疫组织化学研究揭示了SUR1不仅在胰腺β细胞中表达，而且在这些细胞中K_ <ATP>通道的物理作用尚不清楚，这些结果尚不清楚，这些结果表明，Sulfonylureas可以通过SUR1进行效应，并且可以通过sur1进行效应。胰腺β-细胞，使用D-glucose的荧光导数，2-nbdg。通过使用这种新方法，我们透露，葡萄糖代谢以及葡萄糖的摄取对于胰腺β细胞的葡萄糖诱导的胰岛素分泌至关重要，验证了胰岛素分泌中K_ <ATP>通道的重要性。关键作用在癫痫发作的控制中。我们已经表明，缺乏K_ <ATP>通道（KO小鼠）的Kir6.2亚基的突变小鼠在短暂的缺氧后易于抓住。在正常小鼠中，通过打开突触后K_ <ATP>通道在缺氧过程中灭活了SNR神经元活性，而在KO小鼠中，这些神经元的活性得到了增强。这些结果表明，K_ <ATP>通道通过通道的开放对缺氧期间SNR神经元活性产生抑郁症的作用，并且参与了针对广义性癫痫发作的nigral保护机制。

项目成果

Sunaga,Y.,Inagaki,N.,Gonoi,T.,Yamada,Y.,Ishida,H.,Seino,Y. et.al.: "Troglitazone but not pioglitazone affects ATP-sensitive K^+ channel activity."Eur.J.Pharmacol.. 381. 71-76 (1999)

须永 Y.、稻垣 N.、五内 T.、山田 Y.、石田 H.、清乃 Y.

Miki,T.,Inagaki,N.,Nagashima,K.,Gonoi,T.,and Seino,S.: "Potassiun ion channels. Structure and function of ATP-sensitive potassium channels."Academic Press. 492 (1999)

Miki,T.、Inagaki,N.、Nagashima,K.、Gonoi,T. 和 Seino,S.：“钾离子通道。ATP 敏感钾通道的结构和功能。”学术出版社。

Suzuki, M., et al.: "Immuno-localization of sulfonylurea receptor 1 in rat pancreas"Diabetologia. 42. 1204-1211 (1999)

Suzuki, M., et al.：“大鼠胰腺中磺酰脲受体 1 的免疫定位”Diabetologia。

Suzuki, M. , et al.: "Immuno-localization of sulfonylurea receptor 1 in rat pancreas"Diabetologia. 42. 1204-1211 (1999)

Suzuki, M. 等人：“大鼠胰腺中磺酰脲受体 1 的免疫定位”糖尿病学。

稲垣暢也: "受容体型ABCタンパク質SUR."最新医学. 54. 30-37 (1999)

Nobuya Inagaki：“受体型 ABC 蛋白 SUR。”现代医学 54. 30-37 (1999)