Molecular Switches at the Synapse Emerge from Receptor and Kinase Traffic

Hayer, Arnold; Bhalla, Upinder S.

doi:10.1371/journal.pcbi.0010020

Cited by 121 publications

(154 citation statements)

References 64 publications

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“…Several computational models have explored the underlying signaling that controls AMPAR trafficking (16)(17)(18)(19)(20). Nakano et al specifically explored the contribution of dopamine signaling to AMPAR trafficking in striatal neurons (18).…”

Section: Resultsmentioning

confidence: 99%

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

Song

Massenburg

Wenderski

et al. 2013

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

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AMPA-type glutamate receptor (AMPAR) trafficking is essential for modulating synaptic transmission strength. Prior studies that have characterized signaling pathways underlying AMPAR trafficking have identified the cAMP/PKA-mediated phosphorylation of GluA1, an AMPAR subunit, as a key step in the membrane insertion of AMPAR. Inhibition of ERK impairs AMPAR membrane insertion, but the mechanism by which ERK exerts its effect is unknown. Dopamine, an activator of both PKA and ERK, induces AMPAR insertion, but the relationship between the two protein kinases in the process is not understood. We used a combination of computational modeling and live cell imaging to determine the relationship between ERK and PKA in AMPAR insertion. We developed a dynamical model to study the effects of phosphodiesterase 4 (PDE4), a cAMP phosphodiesterase that is phosphorylated and inhibited by ERK, on the membrane insertion of AMPAR. The model predicted that PKA could be a downstream effector of ERK in regulating AMPAR insertion. We experimentally tested the model predictions and found that dopamine-induced ERK phosphorylates and inhibits PDE4. This regulation results in increased cAMP levels and PKA-mediated phosphorylation of DARPP-32 and GluA1, leading to increased GluA1 trafficking to the membrane. These findings provide unique insight into an unanticipated network topology in which ERK uses PDE4 to regulate PKA output during dopamine signaling. The combination of dynamical models and experiments has helped us unravel the complex interactions between two protein kinase pathways in regulating a fundamental molecular process underlying synaptic plasticity.T he strength of synaptic transmission depends on the number of AMPA-type glutamate receptors (AMPARs) localized to the synaptic membrane. The regulated trafficking of AMPARs in and out of the postsynaptic membrane controls the number of synaptic AMPARs and is thought to underlie synaptic plasticity (1). AMPARs are composed of four subunits (GluA1-4), which assemble as homo-or hetero-tetramers to mediate excitatory transmissions in the brain. There are a number of intracellular pathways that regulate signal-initiated trafficking of GluA1-containing AMPARs. For instance, PKA and PKG, the cyclic nucleotide-activated kinases, phosphorylate GluA1 at S845 (2, 3). Phosphorylation of S845 is required for GluA1 synaptic insertion because mutation to A845 prevents GluA1 exocytosis (4). Dopamine, a modulatory neurotransmitter that increases cAMP/ PKA levels, promotes GluA1 phosphorylation at S845 and AMPAR insertion into the plasma membrane (3, 5, 6). Additional signaling pathways influence this process, but the role they play in dopamine-mediated AMPAR trafficking is not known. ERK, a downstream effector of dopamine, promotes AMPAR membrane insertion even though ERK does not directly phosphorylate GluA1 (7,8). The objective of this study was to identify the mechanism by which ERK regulates dopamine-mediated GluA1 membrane insertion. Based on our observation that ERK inhibition decreases dop...

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Section: Resultsmentioning

confidence: 99%

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

Song

Massenburg

Wenderski

et al. 2013

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

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“…A second class of models of synaptic strength stability relies on intricate molecular cascades with multiple stable states (Lisman and Zhabotinsky, 2001;Hayer and Bhalla, 2005;Graupner and Brunel, 2007). However, the model we propose has an advantage over these previous models.…”

Section: Discussionmentioning

confidence: 99%

Dendritic Spine Dynamics Regulate the Long-Term Stability of Synaptic Plasticity

O’Donnell¹,

Nolan²,

Rossum³

2011

J. Neurosci.

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Long-term synaptic plasticity requires postsynaptic influx of Ca 2ϩ and is accompanied by changes in dendritic spine size. Unless Ca 2ϩ influx mechanisms and spine volume scale proportionally, changes in spine size will modify spine Ca 2ϩ concentrations during subsequent synaptic activation. We show that the relationship between Ca 2ϩ influx and spine volume is a fundamental determinant of synaptic stability. If Ca 2ϩ influx is undercompensated for increases in spine size, then strong synapses are stabilized and synaptic strength distributions have a single peak. In contrast, overcompensation of Ca 2ϩ influx leads to binary, persistent synaptic strengths with double-peaked distributions. Biophysical simulations predict that CA1 pyramidal neuron spines are undercompensating. This unifies experimental findings that weak synapses are more plastic than strong synapses, that synaptic strengths are unimodally distributed, and that potentiation saturates for a given stimulus strength. We conclude that structural plasticity provides a simple, local, and general mechanism that allows dendritic spines to foster both rapid memory formation and persistent memory storage.

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“…Other models have dealt with the dynamics of the CaMKII/ protein phosphatase 1 (PP1) system during LTP (Lisman and Goldring, 1988;Coomber, 1998;Bhalla and Iyengar, 1999;Holmes, 2000;Zhabotinsky, 2000;Kubota and Bower, 2001;Lisman and Zhabotinsky, 2001). Recently, Hayer and Bhalla (2005) have published a set of models to study a role of bistability in synaptic plasticity. They took into account trafficking of AMPARs and CaMKII and used pulsatile Ca 2ϩ patterns to induce transitions between the stable states.…”

Section: Methodsmentioning

confidence: 99%

Role of the Neurogranin Concentrated in Spines in the Induction of Long-Term Potentiation

et al. 2006

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). The concentration of calmodulin in neurons is considerably less than the total concentration of the apocalmodulin-binding proteins neurogranin and GAP-43, resulting in a low level of free calmodulin in the resting state. Neurogranin is highly concentrated in dendritic spines. To elucidate the role of neurogranin in synaptic plasticity, we constructed a computational model with emphasis on the interaction of calmodulin with neurogranin, calcineurin, and CaMKII. The model shows how the Ca 2ϩ transients that occur during LTD or LTP induction affect calmodulin and how the resulting activation of calcineurin and CaMKII affects AMPA receptor-mediated transmission. In the model, knockout of neurogranin strongly diminishes the LTP induced by a single 100 Hz, 1 s tetanus and slightly enhances LTD, in accord with experimental data. Our simulations show that exchange of calmodulin between a spine and its parent dendrite is limited. Therefore, inducing LTP with a short tetanus requires calmodulin stored in spines in the form of rapidly dissociating calmodulin-neurogranin complexes.

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Molecular Switches at the Synapse Emerge from Receptor and Kinase Traffic

Cited by 121 publications

References 64 publications

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

ERK regulation of phosphodiesterase 4 enhances dopamine-stimulated AMPA receptor membrane insertion

Dendritic Spine Dynamics Regulate the Long-Term Stability of Synaptic Plasticity

Role of the Neurogranin Concentrated in Spines in the Induction of Long-Term Potentiation

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