ION CHANNEL REGULATION AND MODULATION IN CARDIAC MUSCLE

心肌离子通道的调节和调节

• 批准号: 7953941
• 负责人: JEANNE M. NERBONNE
• 金额: $ 0.87万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7953941
• 关键词: Actins; Action Potentials; Cardiac; Cell surface; Computer Retrieval of Information on Scientific Projects Database; Cytoskeleton; Extracellular Matrix; Funding; Generations; Grant; In Vitro; Individual; Institution; Ion Channel; Macromolecular Complexes; Mass Spectrum Analysis; Mediating; Mink; Multiprotein Complexes; Mus; Muscle Cells; Myocardial; Myocardium; Physiological; Play; Property; Regulation; Research; Research Personnel; Resources; Role; Source; System; Testing; Time; United States National Institutes of Health; Ventricular; biomedical resource; genetic regulatory protein; in vivo; insight; voltage

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multiple types of voltage-gated K+ (Kv) channels with distinct time- and voltage-dependent properties and pharmacological sensitivities have been identified in the mammalian myocardium. This diversity has a physiological significance in that the various Kv channels play distinct roles in controlling action potential waveforms and refractoriness. Although considerable progress has been made in identifying the Kv channel pore-forming (?) subunits that encode diverse cardiac Kv channels, the functional roles of the Kv channel accessory subunits (minK/ MiRPs, Kv?, KChAP, KChIP, DPPX) are rather poorly understood. Studies in heterologous expression systems suggest that Kv accessory subunits can modulate the properties of a variety of Kv ? subunit encoded channels and that each type of Kv channel likely is modulated by multiple accessory subunits. Other recent studies suggest that cardiac Kv (and other) channels function as components of macromolecular protein complexes, comprising pore-forming and accessory subunits, as well as additional regulatory proteins that influence channel properties and mediate interactions with the actin cytoskeleton and the extracellular matrix. To define the physiological roles of the Kv?1, KChlP2 and DPP6 subunits, the studies proposed here will probe directly the functioning of these subunits in the generation of the native Kv channels, lto,f, Ito.s, IK,slow and Iss, in intact cardiac (mouse ventricular) myocytes. The expression levels or the properties of the accessory subunits will be manipulated in vivo and in vitro, and the functional consequences of these manipulations on the properties and cell surface expression of myocardial lto,f, Ito.s, IK,slow and Iss will be determined directly (and simultaneously). The proposed studies will reveal whether individual Kv channel types are regulated/modulated by multiple Kv accessory subunits. In addition, these studies will allow direct testing of the hypothesis that Kv accessory subunits are multifunctional, regulating/modulating the functioning of multiple types of (Kv a subunit encoded) cardiac Kv channels. We anticipate that these studies will provide fundamentally important new insights into the role of Kv channel accessory subunits in the dynamic regulation of cardiac Kv channel macromolecular complexes.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 在哺乳动物心肌中已经确定了多种类型的电压门控的K+（KV）通道，具有不同时间和电压依赖性特性和药理敏感性。这种多样性具有生理意义，因为各种KV通道在控制动作电势波形和难治性方面起着不同的作用。尽管在识别编码各种心脏KV通道的KV通道形成（？）亚基方面取得了长足进展理解不佳。异源表达系统中的研究表明，KV附件亚基可以调节各种KV的性质？亚基编码的通道，每种类型的KV通道都可能由多个附件亚基调制。其他最近的研究表明，心脏KV（和其他）通道充当大分子蛋白复合物的组成部分，包括孔形成和辅助亚基，以及其他影响通道性质并介导与肌动蛋白细胞骨架和细胞外基质的调节蛋白。为了定义KV？1，KCHLP2和DPP6亚基的生理作用，此处提出的研究将直接探测这些亚基在天然KV通道的产生中的功能，完整的心脏（小鼠心室）肌细胞。辅助亚基的表达水平或特性将在体内和体外进行操纵，以及这些操纵对心肌LTO的性质和细胞表面表达的功能后果直接确定（同时）。拟议的研究将揭示单个KV通道类型是否由多个KV辅助亚基调节/调节。此外，这些研究将直接测试KV辅助亚基是多功能的，调节/调节多种类型（KV A亚基编码）心脏KV通道的功能。我们预计，这些研究将对KV通道附件亚基在心脏KV通道大分子复合物的动态调节中的作用提供根本重要的新见解。