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

这项研究将调查被称为神经元的脑细胞如何利用电信号和化学信号进行交流。具体来说，神经元中的一种成分，称为电压感应磷酸酶或VSP，使用电荷直接改变神经元内部的化学物质。然而，VSP如何改变神经元之间的交流仍然未知，对这一过程的更深入了解可能会澄清大脑如何通过神经元之间的交流处理视觉、听觉和触觉等信息。这项研究的结果也可能适用于大脑以外的其他组织，这些组织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批判性思维、解决问题和进行实验的训练。该项目的各个方面将通过儿童和成人的亲身体验与公众分享。为了在蒙大拿州的农村社区获得更广泛的受众，视频会议也将用于分享该项目及其背后的基础科学。膜电位和磷脂酰肌醇磷酸（PIPs）是神经元的重要信号，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这两个信号的蛋白质，它使用电压感应结构域激活磷酸酶结构域，然后以电压依赖的方式使pip去磷酸化。与其他磷酸酶相比，VSP在更快的时间尺度上被激活，因此可以显著影响神经元信号传导。然而，VSP对神经元功能的影响尚不清楚。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，二聚体将被破坏，以确定VSP二聚体与单体对功能的影响。其次，确定VSP异二聚化对催化的影响。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蛋白的理解，并为设计新的电压门控工具（如传感器和酶）奠定了基础。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.