Phosphorylation of Synaptic GTPase-activating Protein (synGAP) by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and Cyclin-dependent Kinase 5 (CDK5) Alters the Ratio of Its GAP Activity toward Ras and Rap GTPases

Walkup, Ward G.; Washburn, Lorraine; Sweredoski, Michael J.; Carlisle, Holly J.; Graham, R.L.; Hess, Sonja; Kennedy, Mary B.

doi:10.1074/jbc.m114.614420

Cited by 74 publications

(97 citation statements)

References 59 publications

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“…This means that simple loss of syn-GAP from the spine would be expected to cause a greater increase in active Rap in the spine and a loss of surface AMPARs, in contrast to the model proposed by Araki et al. Indeed, we found that phosphorylation of synGAP by CaMKII doubles the rate of synGAP’s inactivation of Rap [36]. Thus, one of the same phosphorylation events that promotes detachment of synGAP from the PSD, also causes its rate of inactivation of Rap to increase, not decrease.…”

Section: The Role Of Syngap In Induction Of Ltpcontrasting

confidence: 82%

“…Expression of active Rap in neurons accelerates endocytosis of AMPARs; whereas, expression of active Ras has the opposite effect, accelerating exocytosis of AMPARs [35]. The fold stimulation of Rap inactivation by synGAP is considerably higher than its stimulation of inactivation of Ras [36*]. This means that simple loss of syn-GAP from the spine would be expected to cause a greater increase in active Rap in the spine and a loss of surface AMPARs, in contrast to the model proposed by Araki et al.…”

Section: The Role Of Syngap In Induction Of Ltpmentioning

confidence: 99%

“…Our results suggest that, rather than eliminating the effect of synGAP on Ras and Rap activity, the rheostat-like shifting of the enzymatic specificity of synGAP by phosphorylation would shift the balance toward exocytosis of receptor at the extrasynaptic membrane, as synGAP moves away from the PSD. Interestingly, phosphorylation of another site on synGAP by the homeostatic enzyme Cdk5, increases the rate of inactivation of Ras, without altering the rate of inactivation of Rap, turning the rheostat in the opposite direction, presumably leading to reduction of the number of surface receptors [36]. …”

Section: The Role Of Syngap In Induction Of Ltpmentioning

confidence: 99%

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Biochemistry and neuroscience: the twain need to meet

Kennedy

2017

Current Opinion in Neurobiology

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Neuroscience has come to mean the study of electrophysiology of neurons and synapses, micro and macro-scale neuroanatomy, and the functional organization of brain areas. The molecular axis of the field, as reflected in textbooks, often includes only descriptions of the structure and function of individual channels and receptor proteins, and the extracellular signals that guide development and repair. Studies of cytosolic “molecular machines”, large assemblies of proteins that orchestrate regulation of neuronal functions, have been neglected. However, a complete understanding of brain function that will enable new strategies for treatment of the most intractable neural disorders will require that in vitro biochemical studies of molecular machines be reintegrated into the field of neuroscience.

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Section: The Role Of Syngap In Induction Of Ltpcontrasting

confidence: 82%

Section: The Role Of Syngap In Induction Of Ltpmentioning

confidence: 99%

Section: The Role Of Syngap In Induction Of Ltpmentioning

confidence: 99%

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Biochemistry and neuroscience: the twain need to meet

Kennedy

2017

Current Opinion in Neurobiology

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“…CaMKII links Ca 2+ elevations to downstream cellular targets responsible for LTP and sLTP by phosphorylating diverse substrates (Barria et al, 1997; Murakoshi et al, 2011; Opazo et al, 2010; Walkup et al, 2015; Yang et al, 2013). At its basal state, CaMKII is locked in an inactive state through the binding of a regulatory segment to its substrate binding site.…”

Section: Introductionmentioning

confidence: 99%

CaMKII Autophosphorylation Is Necessary for Optimal Integration of Ca 2+ Signals during LTP Induction, but Not Maintenance

Chang

Parra-Bueno

Laviv

et al. 2017

Neuron

149

223

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SUMMARY CaMKII plays a critical role in decoding calcium (Ca2+) signals to initiate long-lasting synaptic plasticity. However, the properties of CaMKII that mediate Ca2+ signals in spines remain elusive. Here, we measured CaMKII activity in spines using fast-framing two-photon fluorescence lifetime imaging. Following each pulse during repetitive Ca2+ elevations, CaMKII activity increased in a stepwise manner. Thr286 phosphorylation slows the decay of CaMKII and thus, lowers the frequency required to induce spine plasticity by several fold. In the absence of Thr286 phosphorylation, increasing the stimulation frequency results in high peak mutant CaMKIIT286A activity that is sufficient for inducing plasticity. Our findings demonstrate that Thr286 phosphorylation plays an important role in induction of LTP by integrating Ca2+ signals, and it greatly promotes, but is dispensable for the activation of CaMKII and LTP.

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“…Over-expression of different isoforms resulting from various combinations of amino and carboxyl termini has different effects on synaptic strength judged by the amplitude and frequency of mEPSCs (McMahon et al 2012). Moreover, not only CaMKII but also Cdk5 whose translocation to the PSD is mediated by CaMKII regulates the activity of SynGAP toward Ras and Rap differentially (Walkup et al 2015). Thus, CaMKIImediated regulation of SynGAP activity is more complex than initially thought and needs further investigation.…”

Section: Syngapmentioning

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.

show abstract

Phosphorylation of Synaptic GTPase-activating Protein (synGAP) by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and Cyclin-dependent Kinase 5 (CDK5) Alters the Ratio of Its GAP Activity toward Ras and Rap GTPases

Cited by 74 publications

References 59 publications

Biochemistry and neuroscience: the twain need to meet

Biochemistry and neuroscience: the twain need to meet

CaMKII Autophosphorylation Is Necessary for Optimal Integration of Ca 2+ Signals during LTP Induction, but Not Maintenance

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

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