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

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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.