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^+通道是连接细胞代谢状态和膜电位的关键分子。我们已确定胰腺β细胞K_1通道由内向整流子Kir6.2和磺脲受体SUR1亚基组成。我们的结果如下：#我们通过免疫组织化学研究发现，SUR1不仅在胰腺β细胞中表达，而且在胰升糖素阳性细胞、生长抑素阳性细胞或胰腺多肽阳性细胞中也有表达。这些结果表明，磺脲类药物可能通过SUR1对这些细胞产生影响。我们已经建立了一种方法，用D-葡萄糖的荧光衍生物2-NBDG来测量单个活的胰腺β细胞中葡萄糖的转运及其对细胞内各种功能的影响。通过这一新的方法，我们揭示了葡萄糖代谢和葡萄糖摄取在糖诱导的胰腺β细胞胰岛素分泌中起关键作用，从而证实了K通道在胰岛素分泌中的重要性。黑质是大脑中K通道表达最高的区域，在控制癫痫发作中起着关键作用。我们已经证明，缺乏K_&lt；ATP&gt；通道Kir6.2亚单位的突变小鼠(KO小鼠)在短暂缺氧后易发生全身性癫痫发作。在正常小鼠中，SNR神经元的活性在低氧时通过开放突触后K_lt；ATP&gt；通道而失活，而在KO小鼠中，这些神经元的活性增强。这些结果表明，K&lt；ATP&gt；通道通过开放通道而抑制低氧时SNR神经元的活动，并参与黑质对全身性惊厥的保护机制。

项目成果

Yamada, K., et al.: "Measurement of glucose uptake and intracellular calcium concentration in single, living pancreatic β-cells"Journal of Biological Chemistory. 275. 22278-22283 (2000)

Yamada, K. 等人：“单个活胰腺 β 细胞中葡萄糖摄取和细胞内钙浓度的测量”生物化学杂志 275. 22278-22283 (2000)。

Sunaga, Y. , et al.: "Troglitazone but not pioglitazone affects ATP-sensitive K^+ channel activity"European Journal of pharmacology. 381. 71-76 (1999)

Sunaga，Y.，等人：“曲格列酮而不是吡格列酮影响 ATP 敏感的 K^ 通道活性”欧洲药理学杂志。

Furukawa, T., et al.: "Phosphorylation and functional regulation of CIC-2 chloride channels expressed in Xenopus oocytes by M cyclin-dependent protein kinase"Journal of Physiology. (in press). (2002)

Furukawa, T. 等人：“M 细胞周期蛋白依赖性蛋白激酶对非洲爪蟾卵母细胞中表达的 CIC-2 氯通道的磷酸化和功能调节”生理学杂志。

稲垣暢也: "ATP感受性K^+チャネル" 医学のあゆみ. 188. 309-313 (1999)

Nobuya Inagaki：“ATP 敏感 K^+ 通道”医学史 188. 309-313 (1999)。

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.