Ca2+ Dependent K+ Channels: Allosteric Gating

描述（由申请人提供）：本提案的广泛长期目标是了解离子通道门控的机制，这是一种已知可调节各种生理和病理过程的关键分子事件。研究BK型，电压，Ca 2+和Mg 2+依赖的K+通道作为一个模型系统，本建议的重点是研究的分子过程中，电压传感器的运动，Ca 2+或Mg 2+结合耦合到激活门的开放，通过分子内相互作用。具体目标是：一。阐明胞质结构域AC区在Ca 2+依赖性门控中的作用。二.研究结合态Mg ~（2+）与电压传感器之间的相互作用。三.研究S6突变对激活门功能和对电压、Ca ~（2+）和Mg ~（2+）敏感性的影响。BK通道在人类健康中的作用是基于它们被电压、Ca 2+和Mg 2+激活，并且BK通道正被追求为各种疾病的治疗靶点。影响电压和Ca 2+依赖性激活的BK通道突变与癫痫和阵发性运动障碍有关。本申请旨在通过这些刺激来剖析BK通道门控的分子机制，这将为BK通道相关疾病的深入了解和治疗发展提供坚实的基础。近年来的几项研究为我们提供了钾通道Kv1.2，KvAP和MthK的X射线晶体学结构，可以作为BK通道的模型。基于这些结构模型和其他初步结果，将采用多学科的方法，包括电生理学，突变，化学修饰，蛋白质生物化学和动力学建模来实现特定的目标。BK型钾离子通道对脑功能和血液循环很重要。本研究探讨了BK通道的作用机制。这些结果将提高我们对癫痫和高血压等由该通道故障引起的疾病的理解，并促进治疗神经元缺血，创伤和认知能力下降等各种疾病的药物的开发。

DESCRIPTION (provided by applicant): The broad long-term objective of this proposal is to understand the mechanisms of ion channel gating, a key molecular event that is known to regulate a variety of physiological and pathological processes. Studying the BK-type, voltage, Ca2+ and Mg2+ dependent K+ channel as a model system, the focus of this proposal is to investigate the molecular process in which voltage sensor movements, Ca2+ or Mg2+ binding are coupled to the opening of the activation gate through intramolecular interactions. The specific aims are: I. To elucidate the role of a cytosolic domain, the AC region, in Ca2+ dependent gating. II. To investigate the interactions between the bound Mg2+ and the voltage sensor. III. To examine effects of mutations in S6 on the function of the activation gate and the sensitivity to voltage, Ca2+ and Mg2+. The role of BK channels in human health is based on their activation by voltage, Ca2+ and Mg2+, and BK channels are being pursued as a therapeutic target for various diseases. A BK channel mutation that affects voltage and Ca2+ dependent activation is linked to epilepsy and paroxysmal dyskinesia. This application seeks to dissect the molecular mechanism of BK channel gating by these stimuli, which will provide insights into BK channel related diseases and a solid basis for therapeutic developments. Several studies in recent years have provided us with X-ray crystallographic structures of potassium channels Kv1.2, KvAP, and MthK that can serve as models for BK channels. Based on these structural models and other preliminary results, a multi-disciplinary approach, including electrophysiology, mutation, chemical modification, protein biochemistry and kinetic modeling will be used to achieve the specific aims. The BK-type potassium ion channel is important for brain function and blood circulation. This research investigates the mechanism of BK channel function. The results will improve our understanding of diseases caused by the malfunction of this channel such as epilepsy and hypertension, and facilitate the development of drugs treating various diseases such as neuronal ischemia, trauma and cognitive decline.