Voltage-dependent activation in K+ channels

K 通道电压依赖性激活

• 批准号: 6916163
• 负责人: Diane M Papazian
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916163
• 关键词: SDS polyacrylamide gel electrophoresis; Xenopus oocyte; binding sites; conformation; electrophysiology; gene mutation; immunofluorescence technique; ion transport; ionophores; membrane channels; potassium channel; protein structure function; structural biology; voltage gated channel

DESCRIPTION (provided by applicant): In May 2003, the ion channel community was galvanized by the publication of the high resolution X-ray structure of an archaebacterial voltage-dependent K+ channel, KvAP, by MacKinnon and co-workers. KvAP contains sequence hallmarks and functional properties that establish it as a close relative of eukaryotic voltage-dependent K+ channels. The structure of the pore domain in KvAP is similar to KcsA, MthK, and KirBac. In contrast, the structure of the voltage sensor domain in KvAP contains several surprising features that were unanticipated from previous work. Largely influenced by this structure, MacKinnon and co-workers have proposed a new model for voltage-dependent activation in which the voltage sensor domain acts as a hydrophobic paddle that moves through the lipid bilayer during activation. The KvAP structure and the hydrophobic paddle mechanism have generated significant controversy and refocused attention on three essential questions: What is the structure of the voltage sensor? How does it move during activation? How do voltage sensor movements open and close pore gates? Answering these questions is the long-term goal of this research project. The Specific Aims of the proposal are: 1) to investigate the topology of KvAP and proximity between the voltage sensor and pore domains in a native membrane environment; 2) to investigate the mechanism of voltage-dependent activation in KvAP, 3) to investigate voltage sensor/pore domain interactions in Shaker channels, and 4) to investigate voltage sensor conformational changes in ether--gogo (eag) using combined electrophysiological and optical measurements. This proposal describes basic research aimed at understanding the structure and function of voltage-dependent ion channels. The research is likely to have significant health relevance because ion channels have essential roles in the brain, heart, and skeletal muscle.

描述（由申请人提供）：2003年5月，通过Mackinnon及其同事的高分辨率X射线结构的高分辨率X射线结构，由Mackinnon及其同事发表。 KVAP包含序列标志和功能特性，这些特性将其确定为真核电压依赖性K+通道的近亲。 KVAP中孔域的结构类似于KCSA，MTHK和KIRBAC。相比之下，KVAP中电压传感器域的结构包含了几个令人惊讶的特征，这些功能是先前工作中意外的。麦金农和同事在很大程度上受到了这种结构的影响，提出了一种新的模型，用于电压依赖性激活，其中电压传感器结构域充当疏水桨，在激活过程中通过脂质双层移动。 KVAP结构和疏水机制引起了重大争议，并将注意力重新集中在三个基本问题上：电压传感器的结构是什么？它在激活过程中如何移动？电压传感器运动如何打开和关闭孔门？回答这些问题是该研究项目的长期目标。该提案的具体目的是：1）研究本地膜环境中电压传感器和孔域之间KVAP和接近性的拓扑； 2）研究KVAP中电压依赖性激活的机制，3）研究振动弹通道中的电压传感器/孔域相互作用，以及4）使用组合的电物质学和光学测量值研究以太醚 - GOGO（EAG）中的电压传感器构象变化。该建议描述了旨在了解电压依赖性离子通道的结构和功能的基础研究。该研究可能具有重要的健康相关性，因为离子通道在大脑，心脏和骨骼肌中具有重要作用。