Activity-Dependent Transport of the Transcriptional Coactivator CRTC1 from Synapse to Nucleus

Ch’ng, Toh Hean; Uzgil, Besim; Lin, Peter; Avliyakulov, Nuraly K.; O’Dell, Thomas J.; Martin, Kelsey C.

doi:10.1016/j.cell.2012.05.027

Cited by 191 publications

(243 citation statements)

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“…However, studies of E-T coupling have revealed vital roles for not only kinases but also phosphatases in activating CREB-dependent transcription. In a variety of neuron types, LTCCs activate both CaN and CaMKII, which can have either opposing or cooperative roles in regulating CREB-mediated transcription (83,89,90). However, recent studies in sympathetic and cortical neurons found that LTCC Ca 2ϩ influx recruits CaMKII␤ to the channel to transphosphorylate Thr-287 in the autoinhibitory domain of CaMKII␥ and promote Ca 2ϩ -CaM trapping, whereas concomitant activation of CaN dephosphorylates Ser-334 in a nuclear localization sequence on CaMKII␥.…”

Section: Coordinated Kinase and Phosphatase Signaling In Postsynapticmentioning

confidence: 99%

“…In contrast, more prolonged CREB activation (minutes to hours) in response to local LTP induction and restricted Ca 2ϩ influx in dendrites is thought to be mediated by local, postsynaptic CaMKII activation of the ERK pathway followed by slower, longer-distance translocation of ERK signaling from dendrites to nucleus to phosphorylate CREB (87,92,93). In addition, the CREB co-activator CRTC1 is dephosphorylated by CaN in response to LTCC Ca 2ϩ influx triggered by synaptic input to dendrites and then also slowly translocates distally to the nucleus where it is required for CREB-dependent gene expression underlying fear memory (83,94). Thus, although many key players in CREB E-T coupling have been identified, future work must further explore the mechanisms of cellular and synaptic organization that permit signaling to CREB over these different distance and time scales.…”

Section: Coordinated Kinase and Phosphatase Signaling In Postsynapticmentioning

confidence: 99%

“…Several pathways linking acute changes in neuronal activity to persistent alterations in gene transcription rely on local Ca 2ϩ influx through voltage-gated L-type calcium channels (LTCCs) to trigger phosphorylation or dephosphorylation of transcription factors, such as Ca 2ϩ /cAMP-responsive element-binding protein (CREB), CREB-regulated transcriptional coactivator (CRTC1), and nuclear factor of activated T-cells (NFAT) (82)(83)(84). In particular, a privileged role for LTCC Ca 2ϩ signaling to CREB in neuronal excitation-transcription (E-T) coupling associated with LTP/LTD and long-term memory has been known for almost 25 years (85)(86)(87)(88).…”

Section: Coordinated Kinase and Phosphatase Signaling In Postsynapticmentioning

confidence: 99%

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Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

Woolfrey

Dell’Acqua

2015

Journal of Biological Chemistry

117

105

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A central theme in nervous system function is equilibrium: synaptic strengths wax and wane, neuronal firing rates adjust up and down, and neural circuits balance excitation with inhibition. This push/pull regulatory theme carries through to the molecular level at excitatory synapses, where protein function is controlled through phosphorylation and dephosphorylation by kinases and phosphatases. However, these opposing enzymatic activities are only part of the equation as scaffolding interactions and assembly of multi-protein complexes are further required for efficient, localized synaptic signaling. This review will focus on coordination of postsynaptic serine/threonine kinase and phosphatase signaling by scaffold proteins during synaptic plasticity. Control of Synaptic Strength through Balanced Phosphorylation/DephosphorylationA defining aspect of the mammalian brain is its profound capacity for experience-dependent plasticity that modifies the strength of specific synaptic connections between neurons. Two well studied opposing forms of synaptic plasticity at excitatory synapses are long-term potentiation (LTP) 2 and longterm depression (LTD), which strengthen and weaken synapses, respectively. LTP and LTD have been most heavily studied in a brain region called the hippocampus where they support spatial and declarative learning and memory. LTP and LTD are induced by Ca 2ϩ influx through postsynaptic NMDAtype ionotropic glutamate receptors (NMDARs) and are expressed by long-lasting increases or decreases, respectively, in the function of AMPA-type ionotropic glutamate receptors (AMPARs) that mediate the bulk of excitatory synaptic transmission (1, 2). NMDARs are heterotetrameric assemblies most commonly containing two GluN1 and two GluN2A-2D subunits and are permeable to Na ϩ , K ϩ , and Ca 2ϩ . At hippocampal synapses, NMDARs are assembled from GluN1, GluN2A, and GluN2B subunits. AMPARs are heterotetrameric assemblies of GluA1-GluA4 subunits, with most being permeable only to Na ϩ and K ϩ due to inclusion of GluA2 subunits that prevent Ca 2ϩ influx (3). However, hippocampal neurons can also express small numbers of Ca 2ϩ -permeable AMPARs lacking GluA2 subunits (i.e. GluA1 homomers) that primarily reside in extrasynaptic and intracellular locations but can be recruited to synapses during plasticity and following neuronal injuries (4). Intriguingly, there is much commonality in the molecular mechanisms underlying the ostensibly antagonistic processes of LTP and LTD; both require correlated pre-and postsynaptic activity leading to NMDAR Ca 2ϩ influx and are mediated by overlapping sets of enzymes. However, it is the ability of the synapse to detect subtle differences in Ca 2ϩ and other second messengers and efficiently transduce these signals to discrete downstream signaling pathways that permits diametrically opposed outcomes to arise from grossly similar synaptic stimuli.Ultimately, excitatory synaptic plasticity must add, remove, or modify AMPARs to alter synaptic strength. Although AMPAR regulation during plas...

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Section: Coordinated Kinase and Phosphatase Signaling In Postsynapticmentioning

confidence: 99%

Section: Coordinated Kinase and Phosphatase Signaling In Postsynapticmentioning

confidence: 99%

Section: Coordinated Kinase and Phosphatase Signaling In Postsynapticmentioning

confidence: 99%

See 1 more Smart Citation

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

Woolfrey

Dell’Acqua

2015

Journal of Biological Chemistry

117

105

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“…In the invertebrates A. californica and Drosophila melanogaster, the activation of the cascade cAMP-protein kinase A (PKA)-CREB is critical for plasticity and memory formation (Yin et al 1994;Kandel 2012;but see Perazzona 2004). Specifically, cAMP-PKA activation initiates short-term synaptic changes that subsequently link via nuclear translocation of PKA, ERK, and perhaps other kinases to the activation and recruitment of CREB proteins and gene transcription (Bacskai et al 1993;Martin et al 1997;Ch'ng et al 2012). Most of these mechanisms are conserved in the mammalian brain where the CREB-dependent pathway has also been shown to be necessary for long-term memory formation and long-term synaptic plasticity (Benito and Barco 2010;Barco and Marie 2011).…”

Section: Classes Of Transcription Factors Involved In Long-term Memormentioning

confidence: 99%

The Regulation of Transcription in Memory Consolidation

Alberini

Kandel

2014

Cold Spring Harb Perspect Biol

310

257

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De novo transcription of DNA is a fundamental requirement for the formation of long-term memory. It is required during both consolidation and reconsolidation, the posttraining and postreactivation phases that change the state of the memory from a fragile into a stable and long-lasting form. Transcription generates both mRNAs that are translated into proteins, which are necessary for the growth of new synaptic connections, as well as noncoding RNA transcripts that have regulatory or effector roles in gene expression. The result is a cascade of events that ultimately leads to structural changes in the neurons that mediate long-term memory storage. The de novo transcription, critical for synaptic plasticity and memory formation, is orchestrated by chromatin and epigenetic modifications. The complexity of transcription regulation, its temporal progression, and the effectors produced all contribute to the flexibility and persistence of long-term memory formation. In this article, we provide an overview of the mechanisms contributing to this transcriptional regulation underlying long-term memory formation.

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“…Notably, recent studies have identified activity-dependent translocation of specific transcription factors and proteins from the synapse to the nucleus 190,191 . Furthermore, neuronal activity-dependent epigenetic changes in histone modifications and DNA methylation patterns have an important role in modulating synaptic plasticity.…”

Section: Box 3 Activity-dependent Transcription and Translation Of Gementioning

confidence: 99%

Gephyrin: a master regulator of neuronal function?

2014

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The neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligandgated chloride channels-namely, type A GABA (GABA(A)) and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that postsynaptic gephyrin clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, post-translational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules. Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission. Shiva Tyagarajan graduated as a molecular virologist at the Pennsylvania State University (USA) and later trained as a neurobiologist during his post-doctoral studies at the University of Zurich. He is currently a group leader and the research focus of his group is to elucidate molecular and cellular mechanisms that couple transcriptional and post-transcriptional programs to regulate GABAergic synaptic plasticity. 3 AbstractThe neurotransmitters GABA and glycine mediate fast synaptic inhibition by activating ligand-gated Cl  channels, namely the GABA A and glycine receptors. Both types of receptors are anchored postsynaptically by gephyrin, which self-assembles into a scaffold and interacts with the cytoskeleton. Current research indicates that gephyrin postsynaptic clusters are dynamic assemblies that are held together and regulated by multiple protein-protein interactions. Moreover, posttranslational modifications of gephyrin regulate the formation and plasticity of GABAergic synapses, by altering the clustering properties of postsynaptic scaffolds and thereby the availability and function of receptors and other signalling molecules.Here, we discuss the formation and regulation of the gephyrin scaffold, its role in GABAergic and glycinergic synaptic function and the implications for the pathophysiology of brain disorders caused by abnormal inhibitory neurotransmission.On-line summary  Gephyrin is a multi-functional protein, responsible for Moco biosynthesis in all organisms, and for postsynaptic clustering of glycine receptors and GABAA receptors in vertebrate CNS  Gephyrin forms a protein scaffold by self-assembly from trimeric complexes, which interacts with numerous, structurally different proteins, in order to form a high ordered signalling complex in glycinergic and GABAergic synapses  Gephyrin function as a scaffolding protein is regulated by alternate mRNA splicing and by multiple post-transcriptional and posttranslational modifications, which only begin to be understood.  Regulation of gephyrin scaffold by multiple signallin...

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Activity-Dependent Transport of the Transcriptional Coactivator CRTC1 from Synapse to Nucleus

Cited by 191 publications

References 50 publications

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

Coordination of Protein Phosphorylation and Dephosphorylation in Synaptic Plasticity

The Regulation of Transcription in Memory Consolidation

Gephyrin: a master regulator of neuronal function?

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