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

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 PP1γ, but not PP1α, positively regulate synaptic transmission in hippocampal neurons. Moreover, we demonstrated that I-2 enhanced 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 auto-inhibitory 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.

Neuronal protein phosphatase 1β regulates glutamate release, cortical myelination, node of Ranvier formation, and action potential propagation in the optic nerve

“…By using mice with conditional deletion of the individual PP1 isoforms, we found that PP1γ is the major PP1 isoform in CA1 pyramidal neurons that is critical for synaptic transmission and LTP (Foley et al, 2022; Foley et al, 2023). We previously discovered that PP1β in CA1 pyramidal neurons plays a role opposite to that of PP1γ, in synaptic transmission, LTP induction, and memory formation (Foley et al, 2023).…”