The impact of the voltage sensing phosphatase (VSP) dimers on neurons

电压传感磷酸酶（VSP）二聚体对神经元的影响

• 批准号: 2310489
• 负责人: Susy Kohout
• 金额: $ 93.78万
• 依托单位: Rowan University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2310489&HistoricalAwards=false
• 关键词: impact; voltage; sensing; phosphatase; VSP

This research will investigate how brain cells called neurons use both electrical and chemical signals to communicate. Specifically, one component in neurons, called the voltage sensing phosphatase or VSP, uses an electrical charge to directly change the chemistry inside the neuron. However, how VSP then changes neuron communication is still unknown and a greater understanding of this process may clarify how brains process information such as vision, hearing and touch, by communication between neurons. The results from this research may also be applicable to other tissues apart from the brain that are known to use electrical signals to regulate cellular function. Graduate and undergraduate students involved in this project will be trained on how to think critically, solve problems and conduct experiments. Aspects of the project will be shared with the public through hands-on experiences for children and adults. To reach a broader audience within the rural communities of Montana, video conferencing will also be used to share the project and the underlying science behind it. Membrane potential and phosphatidylinositol phosphates (PIPs) are critical signals in neurons, regulating synaptic transmission, ion channels, growth and migration. VSP is the only known protein to directly link both signals, using a voltage sensing domain to activate a phosphatase domain that then dephosphorylates PIPs in a voltage dependent manner. VSP could significantly influence neuronal signaling because it is activated on a faster time scale than other phosphatases. However, the impact of VSP on neuronal function is still unknown. This research aims to determine whether VSP dimerization serves as a regulatory mechanism for VSP activity and specificity. First, the dimer will be disrupted to determine the impact of VSP dimers versus monomers on function. Second, the consequences of VSP heterodimerization on catalysis will be determined. Methods will include electrophysiology, fluorescence, imaging, biochemical techniques, and molecular biology. This research is critical for understanding the molecular mechanism behind VSP, increasing the field’s understanding of voltage sensing proteins and serving as a basis for engineering new voltage-gated tools such as sensors and enzymes.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

这项研究将调查称为神经元的脑细胞如何使用电信号和化学信号进行通信。具体来说，神经元中的一种成分称为电压感应磷酸酶或 VSP，它使用电荷直接改变神经元内部的化学成分。然而，VSP 如何改变神经元通讯仍然未知，对这一过程的更深入了解可能会阐明大脑如何通过神经元之间的通讯处理视觉、听觉和触觉等信息。这项研究的结果也可能适用于除大脑之外的其他已知使用电信号调节细胞功能的组织。参与该项目的研究生和本科生将接受如何批判性思考、解决问题和进行实验的培训。该项目的各个方面将通过儿童和成人的实践经验与公众分享。为了吸引蒙大拿州农村社区更广泛的受众，视频会议还将用于分享该项目及其背后的基础科学。膜电位和磷酸磷脂酰肌醇 (PIP) 是神经元中的关键信号，调节突触传递、离子通道、生长和迁移。 VSP 是唯一已知的直接连接两个信号的蛋白质，它使用电压传感结构域激活磷酸酶结构域，然后以电压依赖性方式使 PIP 去磷酸化。 VSP 可以显着影响神经元信号传导，因为它比其他磷酸酶的激活时间更快。然而，VSP 对神经元功能的影响仍不清楚。本研究旨在确定 VSP 二聚化是否作为 VSP 活性和特异性的调节机制。首先，将破坏二聚体以确定 VSP 二聚体与单体对功能的影响。其次，将确定 VSP 异二聚化对催化的影响。方法包括电生理学、荧光、成像、生化技术和分子生物学。这项研究对于理解 VSP 背后的分子机制、增加该领域对电压传感蛋白的理解以及作为设计传感器和酶等新型电压门控工具的基础至关重要。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。