Dataset Information

The protein kinase M? network as a bistable switch to store neuronal memory.

ABSTRACT:

Background

Protein kinase M? (PKM?), the brain-specific, atypical protein kinase C isoform, plays a key role in long-term maintenance of memory. This molecule is essential for long-term potentiation of the neuron and various modalities of learning such as spatial memory and fear conditioning. It is unknown, however, how PKM? stores information for long periods of time despite molecular turnover.

Results

We hypothesized that PKM? forms a bistable switch because it appears to constitute a positive feedback loop (PKM? induces its local synthesis) part of which is ultrasensitive (PKM? stimulates its synthesis through dual pathways). To examine this hypothesis, we modeled the biochemical network of PKM? with realistic kinetic parameters. Bifurcation analyses of the model showed that the system maintains either the up state or the down state according to previous inputs. Furthermore, the model was able to reproduce a variety of previous experimental results regarding synaptic plasticity and learning, which suggested that it captures the essential mechanism for neuronal memory. We proposed in vitro and in vivo experiments that would critically examine the validity of the model and illuminate the pivotal role of PKM? in synaptic plasticity and learning.

Conclusions

This study revealed bistability of the PKM? network and supported its pivotal role in long-term storage of memory.

SUBMITTER: Ogasawara H

PROVIDER: S-EPMC3022653 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Publications

The protein kinase Mζ network as a bistable switch to store neuronal memory.

Ogasawara Hideaki H Kawato Mitsuo M

BMC systems biology 20101231

<h4>Background</h4>Protein kinase Mζ (PKMζ), the brain-specific, atypical protein kinase C isoform, plays a key role in long-term maintenance of memory. This molecule is essential for long-term potentiation of the neuron and various modalities of learning such as spatial memory and fear conditioning. It is unknown, however, how PKMζ stores information for long periods of time despite molecular turnover.<h4>Results</h4>We hypothesized that PKMζ forms a bistable switch because it appears to consti ...[more]

PMID: 21194445

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Project description:BackgroundTranslation efficiency of certain mRNAs can be regulated through a cytoplasmic polyadenylation process at the pre-initiation phase. A translational regulator controls the polyadenylation process and this regulation depends on its posttranslational modifications e.g., phosphorylation. The cytoplasmic polyadenylation binding protein (CPEB1) is one such translational regulator, which regulates the translation of some mRNAs by binding to the cytoplasmic polyadenylation element (CPE). The cytoplasmic polyadenylation process can be turned on or off by the phosphorylation or dephosphorylation state of CPEB1. A specific example could be the regulation of Calcium/Calmodulin-dependent protein kinase II (?CaMKII) translation through the phosphorylation/dephosphorylation cycle of CPEB1.ResultHere, we show that CPEB1 mediated polyadenylation of ?CaMKII mRNA can result in a bistable switching mechanism. The switch for regulating the polyadenylation is based on a two state model of ?CaMKII and its interaction with CPEB1. Based on elementary biochemical kinetics a high dimensional system of non-linear ordinary differential equations can describe the dynamic characteristics of the polyadenylation loop. Here, we simplified this high-dimensional system into approximate lower dimension system that can provide the understanding of dynamics and fixed points of original system. These simplified equations can be used to develop analytical bifurcation diagrams without the use of complex numerical tracking algorithm, and can further give us intuition about the parameter dependence of bistability in this system.ConclusionThis study provides a systematic method to simplify, approximate and analyze a translation/activation based positive feedback loop. This work shows how to extract low dimensional systems that can be used to obtain analytical solutions for the fixed points of the system and to describe the dynamics of the system. The methods used here have general applicability to the formulation and analysis of many molecular networks.