STRUCTURAL BASIS OF ION CHANNEL OPENING

离子通道开口的结构基础

• 批准号: 2037641
• 负责人: ANTONIUS M VANDONGEN
• 金额: $ 20.98万
• 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/2037641
• 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 该项目的长期目标是阐明分子基础 离子通道行为。 离子通道的一个普遍特性是它们 随机打开和关闭。 配体门控通道和电压门控通道 共享围绕中心排列的子单元或域的通用架构 毛孔。 K 通道和谷氨酸受体的成孔区域似乎 结构保守，表明基本通道功能 像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 对毛孔有贡献。 然而，这种一致的行为似乎被打破了 部分激活的 K 通道下降，导致亚电导 水平。 在这个项目中，各个子单元在塑造通道中的作用 将使用 drk1 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： (i) 确定各个亚基在 渗透和门控； (ii) 确定离子选择性如何受以下因素影响 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，都可以使用突变，其中 活化、渗透或选择性受到严重损害。 意义：在分子水平上理解通道行为将有助于 帮助建立兴奋性和兴奋性障碍的分子基础 神经传递受损。 解释基本方面的能力 就分子结构而言，离子通道功能也是一个 合理药物设计的前提。