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: 2129547
• 负责人: Susy Kohout
• 金额: $ 93.78万
• 依托单位: Montana State University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2129547&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交流。具体而言，神经元中的一个成分（称为电压传感磷酸酶或VSP）使用电荷直接改变神经元内的化学性质。但是，当VSP改变神经元的交流的方式仍然未知，对此过程有更深入的了解可以阐明神经元之间的通信诸如视觉，听力和触摸之类的过程。这项研究的结果也可能适用于除了大脑以外的其他时间，这些时间已知使用电信号来调节细胞功能。参与该项目的研究生和本科生将接受有关如何进行批判性思考，解决问题并进行实验的培训。该项目的各个方面将通过对儿童和成人的动手经验与公众共享。为了吸引蒙大拿州粗糙社区的广泛受众，视频会议也将用于分享该项目和背后的基本科学。膜电位和磷脂酰肌醇磷酸盐（PIPS）是神经元，调节突触传递，离子通道，生长和迁移的关键信号。 VSP是使用电压传感域直接连接两个信号的唯一已知蛋白质，以激活磷酸酶结构域，然后以电压依赖性方式去磷酸化。 VSP可以显着影响神经元信号传导，因为它的时间尺度比其他磷酸酶更快。但是，VSP对神经元功能的影响尚不清楚。这项研究旨在确定VSP二聚化是否是VSP活动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异二聚体对催化的后果。方法将包括电生理学，荧光，成像，生化技术和分子生物学。这项研究对于理解VSP背后的分子机制至关重要，增加了该领域对电压传感器的理解，并作为工程工程新电压门控工具（例如传感器和酶）的基础。该奖项反映了NSF的法定任务，并被认为是通过基金会的智力功能和广泛影响的评估来审查CRITERIA的智力功能和广泛影响。