Analysis of the molecular mechanism underlying the regulation of ATP-sensitive K+ channels by drugs

药物调节ATP敏感K通道的分子机制分析

• 批准号: 16590191
• 负责人: YAMADA Mitsuhiko
• 金额: $ 2.3万
• 依托单位: Shinshu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590191/
• 关键词: ATP-sensitive K^+ channels; sulfonylurea receptors; ABC proteins; nucleotide-binding domains; nucleotides; allosteric model; K^+ channel openers; Kir6.2; クレアチンキナーゼ; 平滑筋

An ATP-sensitive K^+ (K_<ATP>) channel is composed of four sulfonylurea receptors (SUR) and four Kir6.2 subunits. SUR is a member of the ABC protein superfamily and bears 17 transmembrane domains (TMD) and two nucleotide-binding domains (NBD1 and NBD2). K^+ channel openers such as nicorandil activate K_<ATP> channels by binding to the 17^<th> TMD of SUR2. SUR2A and SUR2B differ only in the C-terminal 42 amino acids and have the same TMD and NBDs. Nevertheless, SUR2B/Kir6.2 channels show〜100 times higher sensitivity to nicorandil than SUR2A/Kir6.2 channels.In this study, we found the followings by using the molecular biological technique, the patch clamp method and the model prediction. (A) When KATP channels are activated in the presence of intracellular nucleotides, NBD1 and NBD2 in the same SUR molecule form a dimer. (B) C42 regulates the dimerization of NBDs, and NBDs of SUR2B more easily form the dimer than those of SUR2A. (C) There is an allosteric interaction between the 17^<th> TMD and NBDs. (D) Therefore, SUR2B/Kir6.2 channels show higher sensitivity to nicorandil than SUR2A/Kir6.2 channels.

ATP敏感性K^+（K_<ATP>）通道由四个磺酰脲受体（SUR）和四个Kir6.2亚基组成。SUR是ABC蛋白超家族的成员，具有17个跨膜结构域（TMD）和两个核苷酸结合结构域（NBD 1和NBD 2）。K^+通道开放剂（如尼可地尔）<ATP>通过与SUR 2的17^ TMD结合来激活K_通道<th>。SUR 2A和SUR 2B仅在C-末端42个氨基酸上不同，并且具有相同的TMD和NBD。然而，SUR 2B/Kir6.2通道对尼可地尔的敏感性比SUR 2A/Kir6.2通道高100倍。(A)当KATP通道在胞内核苷酸存在下被激活时，同一SUR分子中的NBD 1和NBD 2形成二聚体。(B)C42调节NBD的二聚化，并且SUR 2B的NBD比SUR 2A的NBD更容易形成二聚体。(C)17^ TMD和NBD之间存在别构相互作用<th>。(D)因此，SUR 2B/Kir6.2通道对尼可地尔的敏感性高于SUR 2A/Kir6.2通道。

项目成果

The nucleotide-binding domains of sulfonylurea receptor 2A and 2B play different functional roles in nicorandil-induced activation of ATP-sensitive K^+ channels.

磺酰脲受体2A和2B的核苷酸结合结构域在尼可地尔诱导的ATP敏感K + 通道激活中发挥不同的功能作用。

• 发表时间: 2004
• 期刊: Mol Pharmacol 65(5)
• 作者: Koshikawa;N.;Seiki;M.(three others).;Yamada M
• 通讯作者: Yamada M

ATP感受性K^+チャネルの分子薬理学

ATP 敏感 K^+ 通道的分子药理学

• 发表时间: 2006
• 期刊: 心電図 26・1
• 作者: Fujino H;Kohzuki H;Takeda I;Tasaki H;Kondo H;Ishida T;Kajiya F;Hisaharu Kohzuki;葛谷恒彦 編著;高野康夫 編;山田充彦
• 通讯作者: 山田充彦

Comparison of kinetic properties of quinidine and dofetilide block of HERG channels.

• DOI: 10.1016/j.ejphar.2004.04.015
• 发表时间: 2004-06
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: K. Tsujimae;Shingo Suzuki;M. Yamada;Y. Kurachi

Phosphatidylinositol 3,4,5-trisphosphate and Ca^<2+>/calmodulin competitively bind to the regulators of G-protein-signaling ---

磷脂酰肌醇3,4,5-三磷酸和Ca^2/钙调蛋白竞争性地结合G蛋白信号调节因子---

• 发表时间: 2005
• 期刊: Biochem.J. 385
• 作者: M;Ishii et al.
• 通讯作者: Ishii et al.

Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes

• DOI: 10.1074/jbc.m405985200
• 发表时间: 2004-10-15
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Hibino, H;Fujita, A;Kurachi, Y
• 通讯作者: Kurachi, Y