%0 Journal Article %A Karl Foley %A Haider Altimimi %A Hailong Hou %A Yu Zhang %A Cody McKee %A Makaía M. Papasergi-Scott %A Hongtian Yang %A Abigail Mayer %A Nancy Ward %A David M. MacLean %A Angus C. Nairn %A David Stellwagen %A Houhui Xia %T PP1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission %D 2022 %R 10.1101/2022.02.10.480004 %J bioRxiv %P 2022.02.10.480004 %X 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 PP1γ, but not PP1α, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhances PP1γ interaction with its major synaptic scaffold, neurabin, by Förster 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.Competing Interest StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2022/02/24/2022.02.10.480004.full.pdf