Localization and Regulation of Shal (Kv4) Potassium Channels

Shal (Kv4) 钾通道的定位和调控

• 批准号: 7632246
• 负责人: SUSAN L TSUNODA
• 金额: $ 25.08万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632246
• 关键词: Action Potentials; Applications Grants; Ataxia; Behavior; Binding; Biochemical; Biological; Biological Assay; Biological Models; Cardiac; Chemicals; Communication; Data; Drosophila genus; Epilepsy; Exhibits; Genetic; Health; Heart; Homologous Gene; Hybrids; Ion Channel; Learning; Long QT Syndrome; Mammals; Maps; Membrane; Memory; Molecular; Myotonia; Nervous System Physiology; Nervous system structure; Neuraxis; Neurons; Paralysed; Play; Potassium Channel; Prevention; Process; Protein Isoforms; Proteins; Public Health; Regulation; Role; Shal channel; Shapes; Site; System; Testing; Transgenic Organisms; Voltage-Gated Potassium Channel; Work; Yeasts; central pattern generator; fly; genetic regulatory protein; in vivo; insight; interdisciplinary approach; interest; mutant; neuronal cell body; novel; protein complex; protein protein interaction

DESCRIPTION (provided by applicant): Our long-term interest is to understand how ion channels are localized to particular sub-cellular sites and regulated by specific protein interactors. In this grant proposal, we focus on the voltage-gated K+ channel, Shal (Kv4), which has been implicated in setting the rhythmic firing of central pattern generators, learning and memory, and shaping the cardiac action potential. Therefore, understanding the mechanisms of Shal K+ channel localization and regulation has important implications for vital processes in the heart and central nervous system. We focus our initial studies on two newly identified interactors, K30 and K29, of Drosophila Shal channels. Both interactors are expressed primarily in the nervous system, co-localize with Shal channels, and exhibit strong and specific binding to the C-terminus of Shal channels. Interestingly, K29 binds to a highly conserved motif required for dendritic targeting of mammalian Shal channels, implicating K29 as a key regulator of Shal channel localization. We will characterize Shal-K30 and Shal-K29 interactions and examine the function of K30 and K29 in the subcellular localization and regulation of Shal channels in vivo. Using Drosophila as a model system will allow us to combine genetic, electrophysiological, cell and molecular biological approaches to study how all identified interactors function in the regulation and subcellular localization of Shal channels. Since strategies and proteins identified are likely to be conserved in mammals, our findings are expected to be significant not only for understanding Drosophila ion channels, but also for mammalian systems. Relevance to public health: Ion channels are the basic components that shape electrical and chemical communication in the nervous system, and the function of ion channels is highly dependent on their subcellular localization and regulation. When ion channels are mis-localized or mis-regulated, consequences are often severe, resulting in conditions such as epilepsy, episodic ataxia, periodic paralysis, myotonia, and Long QT syndrome. Therefore, understanding how ion channels are regulated and localized to subcellular compartments is likely to give important insights into the prevention and treatment of these conditions.

描述(由申请人提供)：我们的长期兴趣是了解离子通道是如何定位到特定的亚细胞位置并由特定的蛋白质相互作用调节的。在这项拨款提案中，我们将重点放在电压门控K+通道Shal(Kv4)上，该通道与中枢模式发生器的节律性放电、学习和记忆以及心脏动作电位的形成有关。因此，了解Shal K+通道的定位和调控机制对心脏和中枢神经系统的重要过程具有重要意义。我们的初步研究集中在两个新发现的果蝇Shal通道的相互作用因子K30和K29上。这两个相互作用因子主要在神经系统中表达，与SHAL通道共定位，并与SHAL通道的C末端显示出强烈和特异的结合。有趣的是，K29与哺乳动物Shal通道树突状靶向所需的高度保守的基序结合，暗示K29是Shal通道定位的关键调节因子。我们将描述Shal-K30和Shal-K29的相互作用，并研究K30和K29在体内Shal通道的亚细胞定位和调节中的作用。以果蝇为模型系统将使我们能够结合遗传学、电生理学、细胞和分子生物学方法来研究所有已识别的相互作用因子如何在Shal通道的调节和亚细胞定位中发挥作用。由于所确定的策略和蛋白质在哺乳动物中可能是保守的，我们的发现不仅对于了解果蝇的离子通道，而且对于哺乳动物的系统都具有重要意义。与公众健康相关：离子通道是塑造神经系统中电子和化学通讯的基本组件，离子通道的功能高度依赖于它们的亚细胞定位和调节。当离子通道错误定位或错误调节时，后果往往是严重的，导致癫痫、发作性共济失调、周期性瘫痪、肌强直和长QT综合征。因此，了解离子通道是如何调节和定位到亚细胞室的，可能会为预防和治疗这些疾病提供重要的见解。