SUR Transmembrane Domain in K(ATP) Channel Function

描述（由申请人提供）：ATP敏感性钾通道（KATP） 是由两个亚基组成的异聚体通道：（I）ATP结合盒 蛋白、磺酰脲A受体（SUR;例如SUR 1、SUR 2），和（ii）抑制剂 整流钾通道亚基（Kir 6;例如Kir6.1、Kir6.2）。 这两种亚基的不同组合产生不同的天然KATP 渠道例如，胰腺中的KATP通道由SUR 1和 Kir6.2 KATP通道作为重要的环节耦合的代谢状态， 细胞膜的兴奋性。在胰腺中， 亚基与隐性疾病持续性高胰岛素血症相关 婴儿期低血糖（PHHI）。PHHI患者具有缺陷的胰腺 KATP通道，导致胰岛素分泌失调。现在已被接受 K1 r6亚基形成通道孔，而SUR亚基赋予 该通道具有新的药理学特征，例如通过 磺酰脲类（SU）和钾通道开放剂（KCO）激活。SUR/Kir6 异聚体通道也显示出对ATP抑制的更高敏感性和更高的 与同聚K1 r6通道相比，细胞表面上的通道密度。 因此，对SUR和K1 r6亚基如何与 对KATP通道的理解至关重要 功能所有的ABC蛋白都由两个跨膜结构域（TMDI和TMBI）组成。 TMDII），每个由六个膜段组成。此外，每个TMD域 随后是胞质核苷酸结合结构域（NBD 1和NBD 2）。苏尔是 与ABC蛋白质家族中的一个亚家族密切相关，包括 多药耐药相关蛋白（MRP）和酵母镉 传送器。该亚家族的成员含有额外的N-末端 跨膜结构域（TMDO），其由五个膜区段组成。 与PHHI表型相关的特异性突变见于 SUR 1的TMDO。在这里，我们提出的证据表明，TMDO的SUR 1影响的， Kir6.2亚基的表面表达和物理门控 这些结果强调了SUR的TMDO的重要性 作为与K1 r6相互作用的重要结构元件。我 本申请旨在阐明TMDO在KATP功能中的作用 频道

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.