Physiological and Pathological Roles of CaMKII-PP1 Signaling in the Brain.

Norifumi Shioda,Kohji Fukunaga

doi:10.3390/ijms19010020

Abstract

Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII), a multifunctional serine (Ser)/threonine (Thr) protein kinase, regulates diverse activities related to Ca2+-mediated neuronal plasticity in the brain, including synaptic activity and gene expression. Among its regulators, protein phosphatase-1 (PP1), a Ser/Thr phosphatase, appears to be critical in controlling CaMKII-dependent neuronal signaling. In postsynaptic densities (PSDs), CaMKII is required for hippocampal long-term potentiation (LTP), a cellular process correlated with learning and memory. In response to Ca2+ elevation during hippocampal LTP induction, CaMKIIα, an isoform that translocates from the cytosol to PSDs, is activated through autophosphorylation at Thr286, generating autonomous kinase activity and a prolonged Ca2+/CaM-bound state. Moreover, PP1 inhibition enhances Thr286 autophosphorylation of CaMKIIα during LTP induction. By contrast, CaMKII nuclear import is regulated by Ser332 phosphorylation state. CaMKIIδ3, a nuclear isoform, is dephosphorylated at Ser332 by PP1, promoting its nuclear translocation, where it regulates transcription. In this review, we summarize physio-pathological roles of CaMKII/PP1 signaling in neurons. CaMKII and PP1 crosstalk and regulation of gene expression is important for neuronal plasticity as well as survival and/or differentiation.

Highlights

Protein phosphorylation, one of the most important post-translational modifications, drives rapid, reversible and extracellular signal-dependent cell signaling
CaMKIIα autonomy is critical for induction and maintenance of hippocampal long-term potentiation (LTP), both of which underlie learning and memory [9,10]
CaMKIIαB and CaMKIIδ3 are expressed in the nucleus [14,18], and their activity is reportedly regulated by the nuclear localization signal (NLS) motif, which, when phosphorylated, prevents nuclear localization

Summary

Introduction

One of the most important post-translational modifications, drives rapid, reversible and extracellular signal-dependent cell signaling. Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII), a multifunctional serine (Ser) and threonine (Thr) kinase [1], regulates diverse Ca2+-mediated neuronal activities, including neurotransmitter release, gene expression, and synaptic plasticity [2,3].

Results

Conclusion