Allosteric Regulation of Ion Channel Gating

离子通道门控的变构调节

• 批准号: 7661441
• 负责人: Christopher J Lingle
• 金额: $ 29.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661441
• 关键词: Address; Allosteric Regulation; Area; Attention; Behavior; Calcium; Categories; Cells; Characteristics; Coupled; Couples; Coupling; Dependence; Electrophysiology (science); Equilibrium; Event; Family; Family member; Homologous Gene; Hormones; Investigation; Ion Channel; Ion Channel Gating; Ions; Length; Ligand Binding; Ligands; Link; Maps; Medical; Membrane; Membrane Potentials; Methods; Molecular; Molecular Biology; Motion; Movement; Muscle relaxation phase; Peptides; Physiological; Play; Potassium; Potassium Channel; Process; Property; Protein Dynamics; Proteins; Regulation; Relative (related person); Research Personnel; Role; Signal Transduction; Smooth Muscle; Stimulus; Structure; Synaptic Transmission; Testing; Tissues; Variant; Voltage-Gated Potassium Channel; Work; base; cell growth regulation; cell type; large-conductance calcium-activated potassium channels; neuronal excitability; programs; sensor; therapeutic target; tool; voltage; voltage gated channel

DESCRIPTION (provided by applicant): The long-term aim of this work is to understand the underlying molecular mechanisms by which naturally occurring stimuli regulate the opening and closing of the BK-type calcium (Ca2+)-activated potassium (K+). A common characteristic shared by BK channels with essentially all other ion channels and also many other categories of protein is that sensing of a physiological stimulus on one part of the protein is coupled to regulation of a key functional property occurring on another part of that protein. In the case of BK channels, sensing of either changes in membrane voltage or changes in cytosolic Ca2+ regulate the activation of ion flux through the channel. The fact that BK channels respond independently to two distinct physiological signals has been an advantage for investigation of the underlying molecular steps that link these processes. This project will focus specifically on two major aspects of how activation of BK channels is regulated. First, the role of conformational changes in the selectivity filter region of the channel in channel activation will be examined. Here, how selectivity filter gating is coupled to either voltage changes or Ca2+ elevations will be examined. Second, the structural features of BK channels that influence coupling between ligand binding and channel activation will be examined. Using methods of electrophysiology combined with molecular biology, this project will take advantage of two closely related ion channels, the BK channel and its pH-regulated homologue, Slo3. Important functional differences between these two channels can be exploited to map the loci responsible for the functional difference. Coupled with mechanistic analyses, information regarding the coupling between gating and ligand dependence can be defined. Together these questions address important general issues that are likely to have broad significance to a wide variety of ion channels. BK channels are of broad importance in the normal functioning of a variety of excitable cells. By responding to both elevations in cytosolic Ca2+ and changes in membrane potentials, BK channels play an important role in the regulation of cellular excitability. Among different tissues, BK channels contribute to regulation of neuronal excitability, smooth muscle relaxation, synaptic transmission and hormone release. Better understanding of the regulation of BK channel function is of potential medical importance, not only because the channels may serve as specific therapeutic targets but also because altered function of particular variants may contribute to unknown pathological conditions.

描述（由申请人提供）：这项工作的长期目标是了解自然发生的刺激调节BK型钙（Ca 2+）激活钾（K+）的开放和关闭的潜在分子机制。BK通道与基本上所有其他离子通道以及许多其他类别的蛋白质共有的共同特征是，蛋白质的一部分上的生理刺激的感测与该蛋白质的另一部分上发生的关键功能性质的调节相耦合。在BK通道的情况下，感测膜电压的变化或胞质Ca 2+的变化调节通过通道的离子通量的激活。BK通道对两种不同的生理信号独立响应的事实对于研究连接这些过程的潜在分子步骤是一个优势。 该项目将特别关注BK通道激活如何调节的两个主要方面。首先，将检查通道激活中通道的选择性过滤区域中的构象变化的作用。在这里，将检查选择性滤波器门控如何与电压变化或Ca 2+升高相耦合。其次，BK通道的结构特征，影响配体结合和通道激活之间的耦合将被检查。使用电生理学与分子生物学相结合的方法，该项目将利用两个密切相关的离子通道，BK通道及其pH调节同源物Slo 3。这两个通道之间的重要功能差异可以被利用来映射负责功能差异的基因座。结合机理分析，可以定义关于门控和配体依赖性之间的耦合的信息。这些问题一起解决了重要的一般性问题，这些问题可能对各种离子通道具有广泛的意义。 BK通道在各种可兴奋细胞的正常功能中具有广泛的重要性。BK通道通过响应胞浆Ca ~（2+）升高和膜电位变化，在调节细胞兴奋性中发挥重要作用。在不同的组织中，BK通道参与调节神经元兴奋性、平滑肌松弛、突触传递和激素释放。更好地了解BK通道功能的调节具有潜在的医学重要性，不仅因为通道可以作为特定的治疗靶点，而且因为特定变体的功能改变可能导致未知的病理状况。