SUR Transmembrane Domain in K(ATP) Channel Function

K(ATP) 通道功能中的 SUR 跨膜结构域

基本信息

批准号：
7057268
负责人：
ROBERT D HARVEY
金额：
$ 23.48万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-04-15 至 2009-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): ATP-sensitive potassium channels (KATP) are heteromeric channels consisting of two subunits: (I) an ATPbinding cassette protein, the SuIfonylUREA receptor (SUR; e.g. SUR1, SUR2), and (ii) an Inwardly rectifying potassium (j about) channel subunit (Kir6; e.g. Kir6.1, Kir6.2). Distinct combinations of these two subunits give rise to different native KATP channels. KATP channels, in the pancreas for example, are formed from SUR1 and Kir6.2. KATP channels serve as important links coupling the metabolic state of a cell to membrane excitability. In the pancreas, mutations in each of the two subunits are correlated with the recessive disorder Persistent Hyperinsulinemic Hypoglycemia of infancy (PHHI). Patients with PHHI possess defective pancreatic KATP channels, resulting in unregulated insulin secretion. It is now accepted that the K1r6 subunit forms the channel pore, while the SUR subunit confers to the channel its novel pharmacological characteristics, such as inhibition by sulfonylureas (SU), and activation by potassium channel openers (KCO). SUR/Kir6 heteromeric channels also show higher sensitivity to ATP inhibition and higher channel density on the cell surface compared to the homomeric K1r6 channels. Hence, a molecular understanding of how the SUR and K1r6 subunits interact with each other is of crucial importance to the understanding of KATP channel function. All ABC proteins are made up of two transmembrane domains (TMDI and TMDII), each consisting of six membrane segments. In addition, each TMD domain is followed by a cytoplasmic nucleotide binding domain (NBD1 and NBD2). SUR is closely related to a subfamily within the ABC family of proteins that includes the multidrug resistance-associated proteins (MRP) and the yeast cadmium transporter. Members of this subfamily contain an extra N-terminal transmembrane domain (TMDO), which is made up of five membrane segments. Specific mutations that are correlated with the PHHI phenotype are found in the TMDO of SUR1. Here, we present evidences that the TMDO of SUR1 affects the surface expression and the gating of the Kir6.2 subunit by physically associating with it. These results underscore the importance of the TMDO of SUR as an important structural element involved in the interactions with K1r6. My application aims to elucidate the role of the TMDO in the function of the KATP channel.

描述（由申请人提供）：ATP 敏感钾通道 (KATP) 是由两个亚基组成的异聚通道：(I) ATP 结合盒蛋白、磺酰脲受体（SUR；例如 SUR1、SUR2），以及 (ii) 内向整流钾(jabout)通道亚基(Kir6；例如Kir6.1、Kir6.2)。这两个亚基的不同组合产生不同的天然 KATP 渠道。 KATP 通道（例如在胰腺中）由 SUR1 和基尔6.2。 KATP通道是耦合代谢状态的重要环节细胞膜的兴奋性。在胰腺中，两者均发生突变亚单位与隐性遗传疾病持续性高胰岛素血症相关婴儿期低血糖（PHHI）。 PHHI 患者的胰腺有缺陷 KATP 通道，导致胰岛素分泌不受调节。现在已被接受 K1r6 亚基形成通道孔，而 SUR 亚基赋予该通道具有新颖的药理特性，例如通过抑制磺酰脲类 (SU) 和钾通道开放剂 (KCO) 的激活。苏尔/基尔6 异聚通道还表现出对 ATP 抑制更高的敏感性和更高的与同聚 K1r6 通道相比，细胞表面的通道密度。因此，从分子角度理解 SUR 和 K1r6 亚基如何与彼此对于理解KATP通道至关重要功能。所有 ABC 蛋白均由两个跨膜结构域（TMDI 和 TMDII），每个由六个膜片段组成。另外，每个TMD域随后是细胞质核苷酸结合域（NBD1 和 NBD2）。苏尔是与 ABC 蛋白质家族中的一个亚家族密切相关，其中包括多药耐药相关蛋白 (MRP) 和酵母镉运输者。该亚家族的成员含有一个额外的 N 末端跨膜结构域（TMDO），由五个膜片段组成。与 PHHI 表型相关的特定突变见于 SUR1 的 TMDO。在这里，我们提供了 SUR1 的 TMDO 影响的证据 Kir6.2 亚基的表面表达和物理门控与之关联。这些结果强调了 SUR TMDO 的重要性作为参与与 K1r6 相互作用的重要结构元件。我的该应用旨在阐明 TMDO 在 KATP 功能中的作用渠道。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Coassembly of different sulfonylurea receptor subtypes extends the phenotypic diversity of ATP-sensitive potassium (KATP) channels.

DOI：
10.1124/mol.108.048355
发表时间：
2008-11
期刊：
MOLECULAR PHARMACOLOGY
影响因子：
3.6
作者：
Wheeler, Adam;Wang, Chuan;Yang, Ke;Fang, Kun;Davis, Kevin;Styer, Amanda M.;Mirshahi, Uyenlinh;Moreau, Christophe;Revilloud, Jean;Vivaudou, Michel;Liu, Shunhe;Mirshahi, Tooraj;Chan, Kim W.
通讯作者：
Chan, Kim W.

Low temperature completely rescues the function of two misfolded K ATP channel disease-mutants.

低温完全挽救了两种错误折叠的 K ATP 通道疾病突变体的功能。