Cell Shape and Negative Links in Regulatory Motifs Together Control Spatial Information Flow in Signaling Networks

Neves, Susana R.; Tsokas, Panayiotis; Sarkar, Anamika; Grace, Elizabeth A.; Rangamani, Padmini; Taubenfeld, Stephen M.; Alberini, Cristina M.; Schaff, James C.; Blitzer, Robert D.; Moraru, Ion I.; Iyengar, Ravi

doi:10.1016/j.cell.2008.04.025

Cited by 280 publications

(332 citation statements)

References 46 publications

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“…The ERK-PDE4 motif could signal in other receptor systems that induce the simultaneous activation of PKA and ERK, such as the beta-adrenergic receptor in the hippocampus (28,31). This motif could also be a potential point of integration for Gs-coupled receptors and ERK activating agents such as growth factors, chemokines, and cytokines in many tissues and cell types.…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…Development of a spatiotemporal model that accounts for diffusive transport along the dendrite with shape change of the spine is an important direction in our future work. Spatial compartmentalization of signaling and shape can affect the dynamics of the activity of different signaling molecules in cell motility (30,(62)(63)(64). Membrane mechanics studies have shown that protein interaction with the membrane cannot only induce a curvature but also, change membrane properties (65).…”

Section: Discussionmentioning

confidence: 99%

“…Dynamical modeling using ordinary differential equations approaches has been used to test hypotheses in silico, generate time courses, and identify emergent properties that would be hard to investigate experimentally. This approach has been used in neuroscience successfully to study different aspects of structural plasticity (21,29,30). In this study, using computational models, we seek to answer the following questions.…”

Section: Significancementioning

confidence: 99%

Paradoxical signaling regulates structural plasticity in dendritic spines

Rangamani

Levy

Khan

et al. 2016

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

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Transient spine enlargement (3-to 5-min timescale) is an important event associated with the structural plasticity of dendritic spines. Many of the molecular mechanisms associated with transient spine enlargement have been identified experimentally. Here, we use a systems biology approach to construct a mathematical model of biochemical signaling and actin-mediated transient spine expansion in response to calcium influx caused by NMDA receptor activation. We have identified that a key feature of this signaling network is the paradoxical signaling loop. Paradoxical components act bifunctionally in signaling networks, and their role is to control both the activation and the inhibition of a desired response function (protein activity or spine volume). Using ordinary differential equation (ODE)-based modeling, we show that the dynamics of different regulators of transient spine expansion, including calmodulin-dependent protein kinase II (CaMKII), RhoA, and Cdc42, and the spine volume can be described using paradoxical signaling loops. Our model is able to capture the experimentally observed dynamics of transient spine volume. Furthermore, we show that actin remodeling events provide a robustness to spine volume dynamics. We also generate experimentally testable predictions about the role of different components and parameters of the network on spine dynamics.CaMKII | dendritic spine | actin

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“…The full MATLAB scripts are available upon request. As we have done in our previous work (39,75,76), most of the model parameters were obtained from the literature. Unknown parameters were constrained using published data, such as the cGMP-dependent activation of PDE2 (22), or data generated by us, such as the cAMP or surface GluA1 increases because of PDE2 inhibition (supplemental Fig.…”

Section: Methodsmentioning

confidence: 99%

Cross-regulation of Phosphodiesterase 1 and Phosphodiesterase 2 Activities Controls Dopamine-mediated Striatal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Trafficking

Song¹,

Tolentino

Sobie

et al. 2016

Journal of Biological Chemistry

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Dopamine, a key striatal neuromodulator, increases synaptic strength by promoting surface insertion and/or retention of AMPA receptors (AMPARs). This process is mediated by the phosphorylation of the GluA1 subunit of AMPAR by cyclic nucleotide-dependent kinases, making cyclic nucleotide phosphodiesterases (PDEs) potential regulators of synaptic strength. In this study, we examined the role of phosphodiesterase 2 (PDE2), a medium spiny neuron-enriched and cGMP-activated PDE, in AMPAR trafficking. We found that inhibiting PDE2 resulted in enhancement of dopamine-induced surface GluA1 expression in dopamine receptor 1-expressing medium spiny neurons. Using pharmacological and genetic approaches, we found that inhibition of PDE1 resulted in a decrease in surface AMPAR levels because of the allosteric activation of PDE2. The cross-regulation of PDE1 and PDE2 activities results in counterintuitive control of surface AMPAR expression, making it possible to regulate the directionality and magnitude of AMPAR trafficking.

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Cell Shape and Negative Links in Regulatory Motifs Together Control Spatial Information Flow in Signaling Networks

Cited by 280 publications

References 46 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

Paradoxical signaling regulates structural plasticity in dendritic spines

Cross-regulation of Phosphodiesterase 1 and Phosphodiesterase 2 Activities Controls Dopamine-mediated Striatal α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptor Trafficking

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