ION CHANNEL REGULATION AND MODULATION IN CARDIAC MUSCLE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 哺乳动物心肌中存在多种类型的电压门控K+(Kv)通道，它们具有明显的时间和电压依赖特性以及药理敏感性。这种多样性具有生理意义，因为不同的Kv通道在控制动作电位波形和不应性方面发挥着不同的作用。尽管在识别Kv通道成孔方面取得了相当大的进展(？)Kv通道附属亚基(Mink/MiRPs，Kv？，KChAP，KChIP，DPPX)的功能作用目前还不清楚。异源表达系统的研究表明，Kv辅助亚基可以调节多种Kv？子单元编码的通道，并且每种类型的Kv通道可能由多个辅助子单元调制。最近的其他研究表明，心脏Kv(和其他)通道是大分子蛋白质复合体的组成部分，包括成孔和辅助亚基，以及影响通道特性并介导与肌动蛋白细胞骨架和细胞外基质相互作用的额外调节蛋白。为了明确Kv？1、KChlP2和DPP6亚基的生理作用，本研究将直接探讨这些亚基在完整的心脏(小鼠)心肌细胞产生天然Kv通道LTO、f、Ito.s、Ik、Slow和ISS中的功能。辅助亚基的表达水平或性质将在体内和体外进行操纵，这些操纵对心肌LTO、f、Ito.s、Ik、Slow和ISS的性质和细胞表面表达的功能后果将直接(并同时)确定。拟议的研究将揭示单个Kv通道类型是否受多个Kv辅助亚基的调节/调制。此外，这些研究将允许直接检验Kv辅助亚基是多功能的假设，调节/调制多种类型(Kv a亚单位编码的)心脏Kv通道的功能。我们预计，这些研究将为Kv通道辅助亚基在心脏Kv通道大分子复合体的动态调节中的作用提供重要的新见解。

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.