PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

Foley, K.; Altimimi, H.; Hou, H.; Zhang, Y.; McKee, C.; Papasergi-Scott, M. M.; Yang, H.; Mayer, A.; Ward, N.; MacLean, D. M.; Nairn, A. C.; Stellwagen, D.; Xia, H.

doi:10.1101/2022.02.10.480004

bioRxiv · 10.1101/2022.02.10.480004

PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

Foley, K.·Altimimi, H.·Hou, H.·Zhang, Y.·McKee, C.·Papasergi-Scott, M. M.·Yang, H.·Mayer, A.·Ward, N.·MacLean, D. M.·Nairn, A. C.·Stellwagen, D.·Xia, H.

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Abstract

Inhibitor-2 (I-2) is a prototypic inhibitor of protein phosphatase-1 (PP1), a major serine-threonine phosphatase that regulates synaptic plasticity and learning and memory. Although I-2 is a potent inhibitor of PP1 in vitro, our previous work has elucidated that, in vivo, I-2 may act as a positive regulator of PP1. Here we show that I-2 and PP1{gamma}, but not PP1, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhances PP1{gamma} interaction with its major synaptic scaffold, neurabin, by Forster resonance energy transfer (FRET)/Fluorescence lifetime imaging microscopy (FLIM) studies, while having a limited effect on PP1 autoinhibitory phosphorylation. Furthermore, our study indicates that the effect of I-2 on PP1 activity in vivo is dictated by I-2 threonine-72 phosphorylation. Our work thus demonstrates a molecular mechanism by which I-2 positively regulates PP1 function in synaptic transmission.

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Foley, K., Altimimi, H., Hou, H., Zhang, Y., McKee, C., Papasergi-Scott, M. M., Yang, H., Mayer, A., Ward, N., MacLean, D. M., Nairn, A. C., Stellwagen, D., Xia, H.. 2022-02-11. PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission. https://doi.org/10.1101/2022.02.10.480004

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