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

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.