Thursday, May 9, 2024
5/9/2024
Reversible phosphorylation is a critical regulatory mechanism for spine morphogenesis, synaptic transmission, long-term potentiation (LTP) and memory formation. Protein phosphatase 1 (PP1) contributes to almost half of the serine/threonine phosphorylation in the mammalian cells, however, the role of three different PP1 isoforms (PP1a, ß, ¿) in these processes is ill defined. PP1ß is not believed to play a role in CNS function. On the other hand, whether PP1a and PP1¿ play a role in synaptic functions have never been determined directly. By using conditional knockout mouse models, we found that PP1ß inhibits synaptic transmission and spine maturation while promotes LTP induction and memory formation. On the other hand, we found that PP1¿ increases synaptic transmission, with PP1a compensating PP1¿. The overarching hypothesis of this application is that myosin phosphatase targeting 1 (MYPT1) and neurabin (Nrb) mediate the distinct effects of PP1ß and PP1¿/a on synaptic function, respectively. In detail, we will test our hypothesis in Aim 1 that PP1ß-MYPT1 holoenzyme inhibits non-muscle myosin IIB-mediated F-actin contraction in inhibiting spine maturation and synaptic transmission. We will determine in Aim 2 that PP1¿, in combination with PP1a, promotes spine maturation, synaptic transmission by interaction with Nrb, a major synaptic scaffolding protein. We will also test our prediction that PP1¿/a achieves these via dephosphorylating Nrb at Ser200. In Aim 3 we will test our prediction that PP1ß inhibits LTD induction, promotes LTP induction and memory formation while PP1¿/a plays an opposite role. We will determine the structure-synaptic function relationship in the roles of PP1ß in synaptic transmission and plasticity, with an emphasis on PP1ß C-termini in which one of the human PP1ß de novo mutations resides. These studies will provide signaling mechanisms of, and structure determinants on, PP1 isoforms in regulating their distinct roles on synaptic functions.
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