AUTHOR=Foley Karl , Altimimi Haider , Hou Hailong , Zhang Yu , McKee Cody , Papasergi-Scott Makaía M. , Yang Hongtian , Mayer Abigail , Ward Nancy , MacLean David M. , Nairn Angus C. , Stellwagen David , Xia Houhui 

TITLE=Protein phosphatase-1 inhibitor-2 promotes PP1γ positive regulation of synaptic transmission

JOURNAL=Frontiers in Synaptic Neuroscience

VOLUME=14

YEAR=2022

URL=https://www.frontiersin.org/journals/synaptic-neuroscience/articles/10.3389/fnsyn.2022.1021832

DOI=10.3389/fnsyn.2022.1021832

ISSN=1663-3563

ABSTRACT=<p>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 <italic>in vitro</italic>, our previous work has elucidated that, <italic>in vivo</italic>, I-2 may act as a positive regulator of PP1. Here we show that I-2 and PP1<italic>γ</italic>, but not PP1α, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhanced PP1<italic>γ</italic> 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 auto-inhibitory phosphorylation. Furthermore, our study indicates that the effect of I-2 on PP1 activity <italic>in vivo</italic> 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.</p>