STRUCTURAL BASIS OF ION CHANNEL OPENING

离子通道开口的结构基础

• 批准号: 2891867
• 负责人: ANTONIUS M VANDONGEN
• 金额: $ 19.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891867
• 关键词: NMDA receptors; Xenopus; Xenopus oocyte; gene mutation; membrane permeability; membrane potentials; polymerase chain reaction; potassium channel; protein structure function; site directed mutagenesis; structural biology; voltage /patch clamp

DESCRIPTION The long term objective of this project is to elucidate the molecular basis of ion channel behavior. A universal property of ion channels is that they open and close stochastically. Both ligand- and voltage-gated channels share a common architecture of subunits or domains arranged around a central pore. The pore-forming regions of K channels and glutamate receptors seem to be structurally conserved, suggesting that fundamental channel functions like permeation and gating may share a molecular basis. Open/close transitions usually involve a coordinated movement of all subunits contributing to the pore. However, this concerted behavior seems to break down in partially activated K channels, giving rise to subconductance levels. In this project the role of individual subunits in shaping channel behavior will be further evaluated using the drk1 K channel and the NMDA receptor as model systems. Specific aims are: (i) To determine the role of individual subunits in permeation and gating; (ii) To determine how ion selectivity is affected by subunit composition; (iii) To determine subunit-subunit interactions in channel activation. For each model system, mutations are available in which activation, permeation, or selectivity are severely compromised. Significance: understanding channel behavior at the molecular level will help establish a molecular basis for disorders in which excitability and neurotransmission are impaired. The ability to explain fundamental aspects of ion channel function in terms of molecular structure is also a prerequisite for rational drug design.

描述 这个项目的长期目标是阐明 离子通道的行为。 离子通道的一个普遍性质是， 打开和关闭随机开关。 配体门控和电压门控通道 共享围绕中心的子单元或域的共同架构 毛孔 K通道和谷氨酸受体的成孔区域似乎 在结构上是保守的，这表明基本的通道功能 类似的渗透和门控可以共享分子基础。 打开/关闭 转换通常涉及所有子单元的协调运动 有助于毛孔。 然而，这种一致的行为似乎打破了 在部分激活的K通道中，引起亚电导 程度. 在这个项目中，单个子单元在塑造通道中的作用 将使用drk 1 K通道和NMDA进一步评估行为 受体作为模型系统。 具体目标是：（一）确定各个分单位在以下方面的作用： 渗透和门控;（ii）确定离子选择性如何受到 亚基组成;（iii）确定亚基-亚基相互作用， 通道激活 对于每个模型系统，突变是可用的，其中 活化、渗透或选择性严重受损。 意义：在分子水平上理解通道行为将 帮助建立一个分子基础的疾病，其中兴奋性和 神经传递受损。 解释基本方面的能力 离子通道功能的分子结构也是一个 合理药物设计的前提。