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Studies of Sulfonylurea Receptors and KATP Channels

磺酰脲受体和KATP通道的研究

基本信息

批准号：
7413684
负责人：
Joseph Bryan
金额：
$ 36.8万
依托单位：
PACIFIC NORTHWEST RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-20 至 2009-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413684
关键词：
ABCC1 gene ATP sensitive potassium channel complex Affect Affinity Labels Amino Acids Antihypertensive Agents Beta Cell Binding Blood Vessels Cell surface Cells Cessation of life Cloning Complex Diabetes Mellitus Energy Metabolism Exhibits Exocytosis Glyburide Goals Grant Head Helix (Snails)Human Insulin Knockout Mice Link Maintenance Measures Membrane MgADP Molecular Muscle Tonus Mutate Mutation Neurons Non-Insulin-Dependent Diabetes Mellitus Nucleotides Patients Persistent Hyperinsulinemia Hypoglycemia of Infancy Pharmaceutical Preparations Physiological Physiological Processes Potassium Potassium Channel Predisposition Probability Property Protein Isoforms Range Regulation Research Research Personnel Signal Transduction Specific qualifier value Striated Muscles Structure Sulfonylurea Compounds Testing Tolbutamide Transmembrane Domain Variant Angina Pectoris Vasospasm Work affinity labeling analog base blood glucose regulation channel blockers ear helix interdisciplinary approach meglitinide member monomer neonatal diabetes mellitus programs receptor stoichiometry sulfonylurea receptor trafficking

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of this program is understanding the basis for regulation of ATP-sensitive potassium KATP channels by nucleotides and pharmacologic agents. KATP channels couple membrane electrical activity to cellular energy metabolism and are key regulators in physiologic processes ranging from control of glucose stimulated insulin release to maintenance of vascular smooth muscle tone. Loss of beta-cell KATP channels is a cause of congenital hyperinsulinism, while sulfonylureas like tolbutamide and glibenclamide, are a mainstay in the treatment of NIDDM. Sulfonylurea receptors, SURs, associate with and regulate the pore forming KIR subunits of KATP channels. Past work has established the stoichiometry of KATP channels, (KIR6.x/SUR)4, and identified SUR domains which specify channel isoform differences including those critical for the action of channel blockers and openers. Without SURs, homomeric KIR6.2 pores have a low open channel probability, POmax, are insensitive to sulfonylureas, display altered bursting, are poorly inhibited by ATP, and not stimulated by MgADP, all properties reversed by co-assembly with an SUR. Recent work demonstrates that the first set of transmembrane helices, TMD0, and a connecting segment of SUR, L0, and the amino terminus of KIR6.x, are critical for the control of slow gating. These segments affinity-label with analogues of glibenclamide arguing for their close proximity. The SUR domain critical for SUR-KIR assembly has been identified. TMD0 interacts with KIRS increasing their Pomax while L0 modulates gating in a bi-directional manner. The goal of the proposed research is to define the inter- and intramolecular interactions involved in the assembly and regulation of KATP channels. We have three specific aims: (1) To define the minimal segment of TMD0 needed to interact with KIR6.2 and determine if this is sufficient to activate (KIR6.2deltaC)4 pores. (2) To test the hypothesis that the amino terminus of KIR6.x interacts with the L0 linker of SURs to control bursting. (3) To define further the sulfonylurea/glibenclamide binding pocket of SUR1, specifically to identify amino acids in proximity to the meglitinide head group.

描述（由申请人提供）：本项目的长期目标是了解核苷酸和药理学试剂调节ATP敏感性钾KATP通道的基础。KATP通道将膜电活动与细胞能量代谢偶联，并且是从控制葡萄糖刺激的胰岛素释放到维持血管平滑肌张力的生理过程中的关键调节剂。β细胞KATP通道的丧失是先天性高胰岛素血症的原因，而磺酰脲类药物如甲苯磺丁脲和格列本脲是治疗NIDDM的主要药物。磺酰脲受体（SURs）与KATP通道的孔形成KIR亚基结合并调节KIR亚基。过去的工作已经建立了KATP通道的化学计量（KIR6.x/SUR）4，并确定了SUR结构域，其指定通道亚型差异，包括通道阻滞剂和开放剂作用的关键。在没有SUR的情况下，同聚体KIR 6.2孔具有低的开放通道概率POmax，对磺酰脲类不敏感，显示出改变的破裂，受ATP的抑制很差，并且不受MgADP的刺激，所有性质都通过与SUR的共组装而逆转。最近的工作表明，第一套跨膜螺旋，TMD 0，和连接段的SUR，L0，和氨基末端的KIR6.x，是控制慢门控的关键。这些片段与格列本脲类似物具有亲和标记，这说明它们非常接近。已经确定了对SUR-KIR组装至关重要的SUR结构域。TMD 0与KIRS相互作用，增加它们的Pomax，而L0以双向方式调节门控。拟议的研究的目标是确定在组装和调节KATP通道所涉及的分子间和分子内的相互作用。我们有三个具体目标：（1）确定与KIR6.2相互作用所需的TMD 0的最小片段，并确定这是否足以激活（KIR6.2 δ C）4孔。(2)检验KIR6.x的氨基末端与SUR的L0接头相互作用以控制爆发的假设。(3)进一步定义SUR 1的磺酰脲类/格列本脲结合口袋，特别是鉴别靠近美格列奈头部基团的氨基酸。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The high-affinity sulfonylurea receptor: distribution, glycosylation, purification, and immunoprecipitation of two forms from endocrine and neuroendocrine cell lines.

高亲和力磺酰脲受体：内分泌和神经内分泌细胞系两种形式的分布、糖基化、纯化和免疫沉淀。

DOI：
10.1021/bi960777y
发表时间：
1996
期刊：
Biochemistry.
影响因子：
0
作者：
Nelson,DA;Bryan,J;Wechsler,S;Clement4th,JP;Aguilar-Bryan,L
通讯作者：
Aguilar-Bryan,L

Molecular biology of adenosine triphosphate-sensitive potassium channels.

DOI：
10.1210/edrv.20.2.0361
发表时间：
1999-04
期刊：
Endocrine reviews
影响因子：
20.3
作者：
L. Aguilar-Bryan;J. Bryan
通讯作者：
L. Aguilar-Bryan;J. Bryan

Role of the amino-terminal transmembrane domain of sulfonylurea receptor SUR2B for coupling to K(IR)6.2, ligand binding, and oligomerization.

磺酰脲类受体 SUR2B 的氨基末端跨膜结构域在与 K(IR)6.2 偶联、配体结合和寡聚化中的作用。

DOI：
10.1007/s00210-011-0708-9
发表时间：
2012
期刊：
Naunyn-Schmiedeberg's archives of pharmacology
影响因子：
0
作者：
Winkler,Marcus;Kühner,Petra;Russ,Ulrich;Ortiz,David;Bryan,Joseph;Quast,Ulrich
通讯作者：
Quast,Ulrich

Incomplete dissociation of glibenclamide from wild-type and mutant pancreatic K ATP channels limits their recovery from inhibition.

格列本脲与野生型和突变型胰腺 K ATP 通道的不完全解离限制了它们从抑制中恢复。