Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP

Herring, Bruce E.; Nicoll, Roger A.

doi:10.1073/pnas.1600179113

Cited by 94 publications

(129 citation statements)

References 33 publications

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“…Indeed, recent evidence suggests that, besides components of native AMPAR complex (Granger et al, 2013), SynGAP and Kalirin/Trio family proteins are other potential CaMKII substrates (Araki et al, 2015; Herring and Nicoll, 2016a). Multiple CaMKII phosphorylation sites were identified in both SynGAP (Araki et al, 2015; Carlisle et al, 2008b; Oh et al, 2004) and Kalirin/Tiam1/Trio family proteins (Fleming et al, 1999; Tolias et al, 2005; Xie et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple CaMKII phosphorylation sites were identified in both SynGAP (Araki et al, 2015; Carlisle et al, 2008b; Oh et al, 2004) and Kalirin/Tiam1/Trio family proteins (Fleming et al, 1999; Tolias et al, 2005; Xie et al, 2007). Molecular replacement of WT protein with SynGAP mutant proteins carrying mutations in CaMKII phosphorylation sites showed impairments in structural plasticity and chemical LTP in primary neurons (Araki et al, 2015) and in LTP in organotypic slice cultures manipulated with Trio/Kalirin (Herring and Nicoll, 2016a). Although multiple CaMKII substrates for LTP may exist, the present study demonstrates that disruption of only TARPγ-8 phosphorylation impairs LTP and performance in a fear-conditioning task.…”

Section: Discussionmentioning

confidence: 99%

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CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory

Park

Chávez

Mineur

et al. 2016

Neuron

113

110

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Summary Protein phosphorylation is an essential step for the expression of long-term potentiation (LTP), a long-lasting, activity-dependent strengthening of synaptic transmission widely regarded as a cellular mechanism underlying learning and memory. At the core of LTP is the synaptic insertion of AMPA receptors (AMPARs) triggered by the NMDA receptor-dependent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). However, the CaMKII substrate that increases AMPAR-mediated transmission during LTP remains elusive. Here, we identify the hippocampus-enriched TARPγ-8, but not TARPγ-2/3/4, as a critical CaMKII substrate for LTP. We found that LTP induction increases TARPγ-8 phosphorylation, and that CaMKII-dependent enhancement of AMPAR-mediated transmission requires CaMKII phosphorylation sites of TARPγ-8. Moreover, LTP and memory formation, but not basal transmission, are significantly impaired in mice lacking CaMKII phosphorylation sites of TARPγ-8. Together, these findings demonstrate that TARPγ-8 is a crucial mediator of CaMKII-dependent LTP and therefore a molecular target that controls synaptic plasticity and associated cognitive functions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory

Park

Chávez

Mineur

et al. 2016

Neuron

113

110

View full text Add to dashboard Cite

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“…Trio, on the other hand, is clearly a more dynamic multi-functional protein, with roles in a variety of neuronal compartments, including growth cones, dendritic spines, and the presynaptic AZ. For example, Drosophila studies have demonstrated that Trio is necessary for the effect of retrograde signals at the neuromuscular junction acting on the motor neuron [39], and recent studies in mammalian systems have demonstrated that Trio has roles in regulating AMPA-type glutamate receptors postsynaptically [77]. Therefore, we would expect that, at any one moment in a neuron, only a small percentage of the available Trio would be bound to Piccolo or Bassoon.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, Wnt signaling might regulate the interaction of Piccolo, Bassoon, Daam1, and Trio both in young neurons, modulating presynaptic assembly and thereafter, in mature neurons, regulating synaptic plasticity. Finally, a recent paper describing Trio’s role in controlling post-synaptic trafficking events underlying long-term potentiation (LTP) clearly showed redundancy between Trio and the highly related protein Kalirin [77]. Thus, future functional studies on Trio in mammalian systems will need to take into account potential redundancy between Trio and Kalirin.…”

Section: Discussionmentioning

confidence: 99%

Trio, a Rho Family GEF, Interacts with the Presynaptic Active Zone Proteins Piccolo and Bassoon

et al. 2016

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Synaptic vesicles (SVs) fuse with the plasma membrane at a precise location called the presynaptic active zone (AZ). This fusion is coordinated by proteins embedded within a cytoskeletal matrix assembled at the AZ (CAZ). In the present study, we have identified a novel binding partner for the CAZ proteins Piccolo and Bassoon. This interacting protein, Trio, is a member of the Dbl family of guanine nucleotide exchange factors (GEFs) known to regulate the dynamic assembly of actin and growth factor dependent axon guidance and synaptic growth. Trio was found to interact with the C-terminal PBH 9/10 domains of Piccolo and Bassoon via its own N-terminal Spectrin repeats, a domain that is also critical for its localization to the CAZ. Moreover, our data suggest that regions within the C-terminus of Trio negatively regulate its interactions with Piccolo/Bassoon. These findings provide a mechanism for the presynaptic targeting of Trio and support a model in which Piccolo and Bassoon play a role in regulating neurotransmission through interactions with proteins, including Trio, that modulate the dynamic assembly of F-actin during cycles of synaptic vesicle exo- and endocytosis.

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“…; Hell ; Shonesy et al . ; Herring and Nicoll ). In this review, we will specifically focus on how enzymatic and structural functions of CaMKII cooperate with each other to facilitate synaptic plasticity of dendritic spines.…”

mentioning

confidence: 98%

Interplay of enzymatic and structural functions of CaMKII in long‐term potentiation

Kim

Saneyoshi

Hosokawa

et al. 2016

Journal of Neurochemistry

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Since the discovery of long-term potentiation (LTP) about a half-century ago, Ca 2+ /CaM-dependent protein kinase II (CaMKII) has been one of the most extensively studied components of the molecular machinery that regulate plasticity. This unique dodecameric kinase complex plays pivotal roles in LTP by phosphorylating substrates through elaborate regulatory mechanisms, and is known to be both necessary and sufficient for LTP. In addition to acting as a kinase, CaMKII has been postulated to have structural roles because of its extraordinary abundance and diverse interacting partners. It now is becoming clear that these two functions of CaMKII cooperate closely for the induction of both functional and structural synaptic plasticity of dendritic spines. Keywords: CaMKII, cytoskeleton, synaptic plasticity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".CaMKII is a serine (S)/threonine (T)-specific protein kinase activated by the Ca 2+ /calmodulin (CaM) complex, consisting of catalytic, regulatory (autoinhibitory/CaM binding) and association domains. Under basal conditions, CaMKII is subject to autoinhibition via an interaction between its kinase and regulatory domains in the absence of Ca 2+ /CaM. In this 'closed' conformation, a pseudosubstrate segment and T286 in the regulatory domain bind to the S (substrate binding) site and T (T286 binding) site in the catalytic domain, respectively, thus preventing the access of substrates. A recent structural study demonstrated that the compact arrangement of inactive CaMKII holoenzyme renders the CaM-binding domain inaccessible, and the strength of the autoinhibitory interaction (degree of 'compactness') depends on the length of linker between the kinase and association domain (Chao et al. 2011). Abbreviations used: AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; CaM, calmodulin; CaMKII, Ca 2+ /calmodulin-dependent protein kinase II; FRET, F€ orster resonance energy transfer; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; GluA1/2, AMPA-type glutamate receptor subunits 1 and 2; GluN1, 2A and 2B, NMDA-type glutamate receptor subunits 1, 2A and 2B; GTPase, guanosine triphosphatase; PDZ, Post synaptic density protein (PSD95), Drosophila disc large tumor suppressor (Dlg1), and Zonula occludens-1 protein (Zo-1); KIF17, kinesin-like protein 17; LTD, long-term depression; LTP, long-term potentiation; NMDA, N-methyl-D-aspartate; SAP97, synapse-associated protein 97; SynGAP, synaptic GTPaseactivating protein.

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Kalirin and Trio proteins serve critical roles in excitatory synaptic transmission and LTP

Cited by 94 publications

References 33 publications

CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory

CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory

Trio, a Rho Family GEF, Interacts with the Presynaptic Active Zone Proteins Piccolo and Bassoon

Interplay of enzymatic and structural functions of CaMKII in long‐term potentiation

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