Modulation of Voltage-gated Calcium Channels and Neuronal Excitability by the Actin-binding Protein KLHL1

智力价值。肌动蛋白结合蛋白是重要的细胞功能调节剂。它们在神经系统中特别重要，它们调节肌动蛋白细胞骨架的功能，而肌动蛋白细胞骨架又调节轴突、树突和突触的形成等过程；囊泡循环，突触活性和突触可塑性。该项目将确定最近发现的神经元肌动蛋白结合蛋白kelch样1（或KLHL1）的功能。特别是，这项研究将扩大我们对这种新型结构蛋白在钙通道功能中的作用的认识，钙通道功能对细胞内通讯和神经传递至关重要。KLHL1通过新发现的途径调节钙通道功能。该项目旨在建立这种新型调制的细胞机制。该项目的具体目标有两个方面：(1)确定消除KLHL1的生理影响。假设是神经元中KLHL1的缺失导致神经元功能的改变。(2)确定KLHL1调控钙通道功能的细胞机制。假设是KLHL1与神经元内的肌动蛋白细胞骨架相互作用，改变内体再循环的速率，导致神经元细胞膜上钙通道的增加。更广泛的影响。这项研究将有助于了解参与神经传递和脑电活动调节的关键蛋白质的功能。该项目的教育部分是招募少数民族本科生，将科学作为一种可能的职业，并使他们参与假设驱动的高水平基础科学研究。将开展活动，鼓励少数民族本科学生参与科学研究和事业，并将包括外展科学研讨会。同时，学生将积极参与全职，动手实验室工作，参加研讨会和数据展示。这将使他们能够学习新技术，发展科学思想，批判性地思考，并体验科学的快感。

ABSTRACT Intellectual merit. Actin-binding proteins are important modulators of cellular function. They are particularly important in the nervous system, where they modulate the function of the actin cytoskeleton, which in turn, modulates processes such as the formation of axons, dendrites and synapses; vesicle recycling, synaptic activity and synaptic plasticity. This project will determine the function of the recently discovered neuronal actin-binding protein Kelch-like 1 (or KLHL1). In particular, this research will expand our knowledge of the role that this novel structural protein plays in calcium channel function, which is critical for intracellular communication and neurotransmission. KLHL1 modulates calcium channel function by a newly identified pathway. This project seeks to establish the cellular mechanism of this novel type of modulation. The specific goals of this project are two-fold: (1) To determine the physiological impact of the elimination of KLHL1. The hypothesis is that the absence of KLHL1 in neurons results in altered neuronal function. (2) To determine the cellular mechanism by which KLHL1 modulates calcium channel function. The hypothesis is that KLHL1 interacts with the actin cytoskeleton within the neurons, altering the rate of endosomal recycling and resulting in the increased presence of calcium channels at the neuronal cell membrane. Broader impacts. This research will contribute to the understanding of the function of key proteins involved in neurotransmission and the modulation of the electrical activity of the brain. The educational component of this project is to recruit under-represented minority undergraduate students to introduce science as a possible career, and to involve them in hypothesis-driven, high-caliber basic scientific research. Activities will be conducted to encourage participation of junior undergraduate minority students in research and careers in science and will include outreach science seminars. In parallel, students will be actively involved in full-time, hands-on laboratory work, seminar participation and data presentation. This will enable them to learn new techniques, to develop scientific ideas, to think critically, and to experience the thrill of science.