MODULATION OF KV CHANNEL BY AN ASSOCIATED BETA SUBUNIT

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 电压依赖性钾通道（Kv）响应于膜电位的变化控制K+通过细胞膜的流动。Kv通道的开放导致膜超极化，其可以减少过度的膜兴奋性或简单地减弱正常的膜活性。Kv通道是神经传导、肌肉收缩和激素分泌等许多基本生物学过程的中心，在细胞中，Kv通道总是与许多其他蛋白质结合形成大分子复合物，而结合蛋白质则调节通道的功能。我们的研究的长期目标是发展一个原子水平上的通道调制机制的理解。在本项目中，我们主要研究β亚基对Kv通道的调节。我们发现β亚基是一种氧化还原酶，它利用NADPH辅因子催化氧化还原反应。我们还发现，与NADPH（还原）或NADP+（氧化）结合的β亚基以不同的方式调节通道功能。我们将解决高分辨率结构的β亚基与整个钾离子通道和细胞内通道结构域，在还原和氧化的形式。我们还将解决β亚基与影响通道功能的小分子调节剂复合的结构。在各种细胞中观察到钾电流的急性变化，并且在启动细胞对缺氧条件和氧化应激的反应中是必不可少的，但其机制通常未知。β亚基可能在细胞内氧化还原化学与通道活性的偶联中起重要作用。我们的研究将解决这种可能性，并导致β亚基的阐明？？的生理作用。

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. Voltage-dependent potassium channels (Kv) control the flow of K+ through the cell membrane in response to changes in membrane potential. The opening of Kv channels causes membrane hyperpolarization that can curtail excessive membrane excitability or simply tone down normal membrane activity. Kv channels are central to many fundamental biological processes, such as nerve conduction, muscle contraction, and hormone secretion.In a cell, Kv channels are always associated with many other proteins to form a macromolecular complex, and the associated proteins modulate channel functions. The long-term goal of our research is to develop an atomic level understanding of channel modulation mechanisms. In this project, we focus on modulation of Kv channel by beta subunit. We have found that beta subunit is an oxidoreductase that utilizes an NADPH cofactor to catalyze a redox reaction. We also found that beta subunit bound with an NADPH (reduced) or an NADP+ (oxidized) modulates channel function differently. We will solve high resolution structures of the beta subunit in complex with the whole potassium channel and with intracellular channel domains, in both reduced and in oxidized forms. We will also solve structures of the beta subunit in complex with small molecule modulators that affect channel functions.Acute changes in potassium current are observed in a variety of cells and are essential in initiating cellular responses to hypoxic conditions and oxidative stresses, but the mechanisms are often unknown. Beta subunit may play an important role in coupling intracellular redox chemistry to channel activities. Our study will address this possibility and lead to the elucidation of beta subunit¿??s physiological role in a cell.