STRUCTURAL BASIS OF ION CHANNEL OPENING

描述 这个项目的长期目标是阐明分子基础。 离子通道的行为。离子通道的一个普遍属性是它们 随机地打开和关闭。配基门控和电压门控通道 共享围绕中心排列的子单元或域的公共体系结构 毛孔。钾通道和谷氨酸受体的成孔区似乎 在结构上是保守的，这表明基本通道功能 就像渗透和门控一样，可能有共同的分子基础。打开/关闭 转换通常涉及所有亚基的协调运动 对毛孔有贡献。然而，这种协调一致的行为似乎打破了 在部分激活的K通道中向下，产生次导 级别。在本项目中，单个亚基在形成通道中的作用 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：(1)确定个别亚基在 渗透和门控；(Ii)确定离子选择性如何受 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，都有突变，其中 活化、渗透或选择性严重受损。 意义：在分子水平上理解渠道行为将 帮助建立兴奋性和兴奋性紊乱的分子基础 神经传递功能受损。解释基本方面的能力 在分子结构方面的离子通道功能也是 合理设计药物的前提条件。

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.