In Vitro Reconstitution of a CaMKII Memory Switch by an NMDA Receptor-Derived Peptide

Urakubo, Hidetoshi; Sato, Makihiko; Ishii, Shin; Kuroda, Shinya

doi:10.1016/j.bpj.2014.01.026

Cited by 30 publications

(48 citation statements)

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“…5, information is stored because a dynamic process maintains the level of phosphorylated CaMKII. The plausibility of this dynamic process was tested in reconstitution experiments using purified proteins (Urakubo et al, 2014). It was shown that a simple chemical system containing CaMKII, calmodulin, protein-phosphatase 1, and a peptide fragment containing the CaMKII-binding site on the NMDA channel could function as a switch.…”

Section: Discussionmentioning

confidence: 99%

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

Rossetti

Banerjee

Kim

et al. 2017

Neuron

121

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Summary The abundant synaptic protein, CaMKII, is necessary for long-term potentiation (LTP) and memory. However, whether CaMKII is required only during initial processes or whether it also mediates memory storage remains unclear. The most direct test of a storage role is the erasure test. In this test, a putative memory molecule is transiently inhibited after learning. The key prediction is that this should produce persistent memory erasure. We conducted this test using transient viral (HSV) expression of dominant-negative CaMKII-alpha (K42M) in the hippocampus. This produced persistent erasure of conditioned place avoidance. As an additional test, we found that expression of activated CaMKII (T286D/T305A/T306A) impaired place avoidance, a result not expected if a process other than CaMKII stores memory. Our behavioral results, taken together with prior experiments on LTP, strongly support a critical role of CaMKII in LTP maintenance and memory storage.

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Section: Discussionmentioning

confidence: 99%

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

Rossetti

Banerjee

Kim

et al. 2017

Neuron

121

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“…Recent reconstitution experiments directly demonstrate this mechanism (Urakubo et al, 2014). These experiments utilized purified CaMKII, protein phosphatase 1 (PP1), and a peptide fragment of NR2B.…”

Section: Principle 1: Intersubunit Autophosphorylation Of T286 Maintamentioning

confidence: 95%

“…An important finding of the reconstitution experiments of (Urakubo et al, 2014) is that the switch was not stable in the absence of NR2B (see also (Bradshaw et al, 2003)). From a theoretical standpoint, this is not unexpected, given that the experiments were conducted under conductions of CaMKII holoneyzme concentration (2.7 micromolar) much less than the concentration in the PSD (~50 micromolar); thus, the saturation of PP1 that promotes the stability of the on state was below what would be expected in the PSD (Zhabotinsky, 2000).…”

Section: Principle 2: In the On State Dephosphorylation Of T286 Becomentioning

confidence: 99%

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Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex

Lisman¹,

Raghavachari²

2015

Brain Research

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Memory involves the storage of information at synapses by an LTP-like process. This information storage is synapse specific and can endure for years despite the turnover of all synaptic proteins. There must, therefore, be special principles that underlie the stability of LTP. Recent experimental results suggest that LTP is maintained by the complex of CaMKII with the NMDAR. Here we consider the specifics of the CaMKII/NMDAR molecular switch, with the goal of understanding the biochemical principles that underlie stable information storage by synapses. Consideration of a variety of experimental results suggests that multiple principles are involved. One switch requirement is to prevent spontaneous transitions from the off to the on state. The highly cooperative nature of CaMKII autophosphorylation by Ca2+ (Hill coefficient of 8) and the fact that formation of the CaMKII/NMDAR complex requires release of CaMKII from actin are mechanisms that stabilize the off state. The stability of the on state depends critically on intersubunit autophosphorylation, a process that restores any loss of pT286 due to phosphatase activity. Intersubunit autophosphorylation is also important in explaining why on state stability is not compromised by protein turnover. Recent evidence suggests that turnover occurs by subunit exchange. Thus, stability could be achieved if a newly inserted unphosphorylated subunit was autophosphorylated by a neighboring subunit. Based on other recent work, we posit a novel mechanism that enhances the stability of the on state by protection of pT286 from phosphatases. We posit that the binding of the NMNDAR to CaMKII forces pT286 into the catalytic site of a neighboring subunit, thereby protecting pT286 from phosphatases. A final principle concerns the role of structural changes. The binding of CaMKII to the NMDAR may act as a tag to organize the binding of further proteins that produce the synapse enlargement that underlies late LTP. We argue that these structural changes not only enhance transmission, but also enhance the stability of the CaMKII/NMDAR complex. Together, these principles provide a mechanistic framework for understanding how individual synapses produce stable information storage.

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“…In addition, CaMKII possesses bi-stability in their model, in which the model’s intracellular signaling was adopted from a previous model with CaMKII bi-stability24. It should be noted here that CaMKII has sometimes been hypothesized to function as a bi-stable memory element at postsynaptic spines during the induction of long-term potentiation245960101, while such bi-stable character has not been observed by an in vivo imaging of CaMKII activity in dendritic spines102. Related to this controversy, our reverse-engineered model suggested monotonical dose-response of CaMKII, instead of more complicated one like with hysteresis; the former never produces bi-stability.…”

Section: Discussionmentioning

confidence: 99%

Multi-phasic bi-directional chemotactic responses of the growth cone

Naoki

Nishiyama

Togashi

et al. 2016

Sci Rep

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The nerve growth cone is bi-directionally attracted and repelled by the same cue molecules depending on the situations, while other non-neural chemotactic cells usually show uni-directional attraction or repulsion toward their specific cue molecules. However, how the growth cone differs from other non-neural cells remains unclear. Toward this question, we developed a theory for describing chemotactic response based on a mathematical model of intracellular signaling of activator and inhibitor. Our theory was first able to clarify the conditions of attraction and repulsion, which are determined by balance between activator and inhibitor, and the conditions of uni- and bi-directional responses, which are determined by dose-response profiles of activator and inhibitor to the guidance cue. With biologically realistic sigmoidal dose-responses, our model predicted tri-phasic turning response depending on intracellular Ca2+ level, which was then experimentally confirmed by growth cone turning assays and Ca2+ imaging. Furthermore, we took a reverse-engineering analysis to identify balanced regulation between CaMKII (activator) and PP1 (inhibitor) and then the model performance was validated by reproducing turning assays with inhibitions of CaMKII and PP1. Thus, our study implies that the balance between activator and inhibitor underlies the multi-phasic bi-directional turning response of the growth cone.

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In Vitro Reconstitution of a CaMKII Memory Switch by an NMDA Receptor-Derived Peptide

Cited by 30 publications

References 50 publications

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

Biochemical principles underlying the stable maintenance of LTP by the CaMKII/NMDAR complex

Multi-phasic bi-directional chemotactic responses of the growth cone

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