Autonomous CaMKII Mediates Both LTP and LTD Using a Mechanism for Differential Substrate Site Selection

Coultrap, Steven J.; Freund, Ronald K.; O’Leary, Heather; Sanderson, Jennifer L.; Roche, Katherine W.; Dell’Acqua, Mark L.; Bayer, K. Ulrich

doi:10.1016/j.celrep.2014.01.005

Cited by 176 publications

(265 citation statements)

References 44 publications

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“…The delay may indicate that several Thr286 sites on the CaMKII complex, which normally exists as a 12-subunit holoenzyme (34,35), require dephosphorylation for the holoenzyme to move with respect to the NMDARcd. Our immunoprecipitation experiments support the view that agonist binding to the NMDAR leads to Thr286 dephosphorylation of associated CaMKII without its unbinding to the NMDARcd, suggesting a reorientation of CaMKII within the complex to a new location, maintaining catalytic activity (20) with potentially different substrates, necessary for LTD (28,36).…”

Section: Discussionsupporting

confidence: 65%

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Aow

Doré

Malinow

2015

Proc. Natl. Acad. Sci. U.S.A.

112

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The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity.A gonist binding to the NMDAR is required for two major forms of synaptic plasticity: long-term potentiation (LTP) and longterm depression (LTD) (1). Surprisingly, activation of NMDARs can produce plasticity in opposite directions, with LTP enhancing transmission and LTD reducing transmission. A model was developed (2, 3) to explain how activation of NMDAR could produce these opposing phenomena: strong stimuli during LTP induction drive a large flux of Ca 2+ through NMDARs, leading to a large increase in intracellular calcium ion concentration ([Ca 2+ ] i ) that activates one series of biochemical steps leading to synaptic potentiation; a weaker stimulus during LTD induction drives a more reduced flux of Ca 2+ through NMDARs, producing a modest increase in [Ca 2+ ] i that activates a different series of biochemical steps, leading to synaptic depression. However, this model is not consistent with recent studies suggesting that no change in [Ca 2+ ] i is required for LTD, and instead invokes metabotropic signaling by the NMDAR (4). Studies supporting an ion-flow-independent role for NMDARs in LTD (4-7) and other processes (7-13) stand in contrast to studies proposing that flow of Ca 2+ through NMDAR is required for LTD (14) Results Transient NMDAR Agonist Binding Without Ion Flux DepressesSpontaneous Excitatory Postsynaptic Currents. In the accompanying study (16), Förster resonance energy transfer (FRET)-fluorescence lifetime imaging microscopy (FLIM) imaging was used to show that agonist binding to the NMDAR produces conformational movement of the NMDARcd. This effect displayed the same pharmacological profile as the electrically induced LTD recently published (4) and independently confirmed (7), suggesting that the conformational changes measured in the NMDARcd are associated with LTD induction. To test whether the stimulation protocol that drives conformational changes in the NMDARcd produces changes in synaptic function, spontaneous synaptic activity was recorded in primary hippocampal neurons, and NMDA was transiently applied in the presence of 7CK, a noncompetit...

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Section: Discussionsupporting

confidence: 65%

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Aow

Doré

Malinow

2015

Proc. Natl. Acad. Sci. U.S.A.

112

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“…The results of this study demonstrate that NO-induced CaMKII autonomy is a novel regulatory mechanism for an enzyme critically involved in mediating synaptic plasticity (1,(3)(4)(5) and ischemic/excitotoxic neuronal cell death (6, 7). Indeed, CaMKII inhibition protected also from neuronal cell death directly induced by NO donors.…”

Section: Discussionmentioning

confidence: 91%

“…This mechanism allows for a molecular memory of past Ca 2ϩ -signals by the autonomous activity, but may also prevent complete uncoupling from subsequent cellular Ca 2ϩ signaling. However, physiological functions for such further stimulation of autonomous CaMKII have been described only very recently, specifically in determining whether autonomous CaMKII promotes potentiation or depression of synaptic strength (5).…”

mentioning

confidence: 99%

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

Coultrap

Bayer

2014

Journal of Biological Chemistry

146

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Background: Ca 2ϩ -independent autonomous CaMKII activity and nitric oxide (NO) signaling regulate neuronal function and death. Results: NO generated autonomous CaMKII activity by Ca 2ϩ /CaM-dependent S-nitrosylation, and CaMKII inhibition protected from NO-induced neuronal cell death. Conclusion: NO-mediated regulation of CaMKII contributes to its pathological functions. Significance: S-Nitrosylation is a novel path to CaMKII autonomy that connects Ca 2ϩ -and NO signaling.

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“…Electrophysiology-Hippocampal recordings were collected as described previously (1,9). Briefly, slices were placed in a recording chamber and submerged in recirculating ACSF at 31-32°C.…”

Section: Methodsmentioning

confidence: 99%

The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength

Barcomb¹,

Hell

Benke

et al. 2016

Journal of Biological Chemistry

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Learning, memory, and cognition are thought to require normal long-term potentiation (LTP) of synaptic strength, which in turn requires binding of the Ca 2؉ /calmodulin-dependent protein kinase II (CaMKII) to the NMDA-type glutamate receptor (NMDAR) subunit GluN2B. For LTP induction, many additional required players are known. Here we tested the hypothesis that CaMKII/GluN2B binding also mediates the more elusive maintenance of synaptic strength. Intriguingly, the CaMKII inhibitor tatCN21 reduces synaptic strength only at high concentrations necessary for CaMKII/NMDAR disruption (20 M) but not at lower concentrations sufficient for kinase inhibition (5 M). However, increased concentration also causes unrelated effects. Thus, to distinguish between correlation and causality, we used a pharmacogenetic approach. In a mouse with a mutant NMDAR GluN2B subunit that is CaMKII binding-incompetent, any tatCN21 effects that are specific to the CaMKII/GluN2B interaction should be abolished, and any remaining tatCN21 effects have to be nonspecific (i.e. mediated by other targets). The results showed that the persistent reduction of synaptic strength by transient application of 20 M tatCN21 had a nonspecific presynaptic component (on fiber volley amplitude) that was unrelated to the CaMKII/GluN2B interaction or CaMKII activity. However, the remaining component of the persistent tatCN21 effect was almost completely abolished in the GluN2B mutant mouse. These results highlight the requirement for stringent pharmacogenetic approaches to separate specific ontarget effects from nonspecific off-target effects. Importantly, they also demonstrate that the CaMKII/GluN2B interaction is required not only for normal LTP induction but also for the maintenance of synaptic strength.The Ca 2ϩ /calmodulin-dependent protein kinase II (CaM-KII) 3 and the NMDA-type glutamate receptor (NMDAR) are central mediators of long-term potentiation (LTP) and depression (LTD), forms of synaptic plasticity thought to underlie learning, memory, and cognition (1; for a review, see Refs. 2-5). Many additional molecular players have been implicated in the induction of these changes of synaptic strength (4, 6, 7); however, the mechanisms responsible for then maintaining synaptic strength have been elusive. CaMKII has been hypothesized to mediate not only LTP induction but also the maintenance of synaptic strength (2-4), as Ca 2ϩ influx through NMDARs triggers CaMKII autophosphorylation at Thr-286 to generate Ca 2ϩ -independent "autonomous" kinase activity, a process that can provide "molecular memory" of the initial Ca 2ϩ stimulus (8, 9). However, although CaMKII Thr-286 phosphorylation is indeed required for LTP (10), this requirement is for induction rather than maintenance. Thr-286 phosphorylation of synaptic CaMKII is reversed within 2 min of LTP induction (11), and CaMKII inhibition after LTP induction does not affect maintenance (9). Another kinase that has received prominent attention as a "memory kinase" is PKM, and its inhibitor myrZIP does indeed reve...

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Autonomous CaMKII Mediates Both LTP and LTD Using a Mechanism for Differential Substrate Site Selection

Cited by 176 publications

References 44 publications

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Nitric Oxide Induces Ca2+-independent Activity of the Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII)

The CaMKII/GluN2B Protein Interaction Maintains Synaptic Strength

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