FUNCTIONAL DOMAINS OF K+ CHANNEL SUBUNIT PROTEINS

电压门控钾通道通过响应于细胞中增加的电活动门控打开钾通道电导来调节可兴奋细胞（例如神经和肌肉细胞）的电活动。由于细胞内钾含量较高，钾离子通过这个孔的损失使细胞内部更加消极，抑制进一步的电活动。钾通道的问题与许多疾病有关，包括：心律失常、癫痫和电节律紊乱。针对钾通道的药物被用于治疗各种疾病，包括高血压、多发性硬化症和糖尿病。此外，钾通道的结构与其他离子通道相似，如钠和钙通道。在这项研究中，我们将继续研究不同钾通道家族编码的独特特性。这些研究揭示了通道细胞质表面的特定结构域如何参与通道组装、功能以及与其他细胞信号系统相互作用的调节。在具体目标1中，我们将继续我们的研究，通过完成Shaker型钾通道的细胞质N-末端的结构测定来确定这些通道的结构，并确定其他蛋白质如何与该结构相互作用。在特定目标2中，我们将重点转移到全长通道，以确定细胞质N-末端如何整合到全通道中，以及细胞质N-末端的结构是否与通道门控状态偶联。最后，在具体目标3中，将研究Zn 2+离子在非Shaker型钾通道中的作用。结构性Zn 2+离子的存在是非Shaker钾通道和Shaker型通道之间的一个显著差异。我们的研究将确定这种Zn 2+离子在这些通道中的作用。通过完成这些研究，我们将大大扩展我们对电压门控钾通道结构的理解，以及它们作为可兴奋细胞细胞生物学一部分的作用。

Voltage-gated potassium channels regulate the electrical activity of excitable cells, such as nerve and muscle cells, by gating open a potassium channel conductance in response to increased electrical activity in the cell. Because potassium is high inside the cell, the loss of potassium ions through this pore makes the inside of the cell more negative, inhibiting further electrical activity. Problems in potassium channels have been linked to numerous diseases, including: cardiac arrhythmias, epilepsy, and electrical rhythm disturbances. Drugs targeting potassium channels are used to treat a variety of disorders including hypertension, multiple sclerosis, and diabetes. In addition, the structure of potassium channels are similar to other ion channels, such as sodium and calcium channels. In this study we are continuing our investigation into the question of what unique properties are encoded in the different families of potassium channels. These studies are revealing how specific domains on the cytoplasmic surfaces of the channels are involved in the regulation of channel assembly, function, and the interactions with other cellular signaling systems. In Specific Aim 1, we will continue our studies determining the structures of these channels by completing the structural determination of the cytoplasmic N-terminus of a Shaker type potassium channel, and determining how other proteins interact with this structure. In Specific Aim 2, we will move our focus to the full length channel to determine how the cytoplasmic N-terminus is integrated into the full channel, and whether the structure of the cytoplasmic N-terminus is coupled to channel gating status. Finally,. In Specific Aim 3 will examine what the role of Zn2+ ions is in non-Shaker type potassium channels. The presence of a structural Zn2+ ion is one striking difference between non-Shaker potassium channels and Shaker type channels. Our studies will determine what the role of this Zn2+ ion is in these channels. By completing these studies we will significantly extend our understanding of the structures of voltage-gated potassium channels, and their roles as part of the cell biology of excitable cells.