A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

Walkup, Ward G.; Mastro, Tara L.; Schenker, Leslie T.; Vielmetter, Jost; Hu, Rebecca; Iancu, Ariella; Reghunathan, Meera; Bannon, Barry Dylan; Kennedy, Mary B

doi:10.7554/elife.16813

Cited by 64 publications

(73 citation statements)

References 72 publications

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“…Ras in turn promotes postsynaptic delivery of AMPARs (Zhu et al, ). Recent work now finds that CaMKII phosphorylation of SynGAP leads to displacement of SynGAP from the postsynaptic site, thereby fostering LTP (Araki et al, ; Walkup et al, ).…”

Section: Emerging Camkii Targets In Ltp: Syngap and Neuroligin‐1mentioning

confidence: 99%

“…Ras in turn promotes postsynaptic delivery of AMPARs (Zhu et al, 2002). Recent work now finds that CaMKII phosphorylation of SynGAP leads to displacement of SynGAP from the postsynaptic site, thereby fostering LTP (Araki et al, 2015;Walkup et al, 2016). Finally, the postsynaptic cell adhesion protein neuroligin-1 is important for synapse formation by interacting with presynaptic neurexin (Scheiffele et al, 2000).…”

Section: Emerging Camkii Targets In Ltp: Syngap and Neuroligin-1mentioning

confidence: 99%

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Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

2018

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The synapse transmits, processes, and stores data within its tiny space. Effective and specific signaling requires precise alignment of the relevant components. This review examines current insights into mechanisms of AMPAR and NMDAR localization by PSD‐95 and their spatial distribution at postsynaptic sites to illuminate the structural and functional framework of postsynaptic signaling. It subsequently delineates how β2 adrenergic receptor (β2 AR) signaling via adenylyl cyclase and the cAMP‐dependent protein kinase PKA is organized within nanodomains. Here, we discuss targeting of β2 AR, adenylyl cyclase, and PKA to defined signaling complexes at postsynaptic sites, i.e., AMPARs and the L‐type Ca2+ channel Cav1.2, and other subcellular surface localizations, the role of A kinase anchor proteins, the physiological relevance of the spatial restriction of corresponding signaling, and their interplay with signal transduction by the Ca2+‐ and calmodulin‐dependent kinase CaMKII. How localized and specific signaling by cAMP occurs is a central cellular question. The dendritic spine constitutes an ideal paradigm for elucidating the dimensions of spatially restricted signaling because of their small size and defined protein composition.

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Section: Emerging Camkii Targets In Ltp: Syngap and Neuroligin‐1mentioning

confidence: 99%

Section: Emerging Camkii Targets In Ltp: Syngap and Neuroligin-1mentioning

confidence: 99%

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

2018

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“…In a second biochemical study, we uncovered a function of synGAP unrelated to its GAP activity [37**]. We found that phosphorylation of synGAP by CaMKII at several sites progressively reduces the affinity of synGAP binding to all three PDZ domains of PSD-95.…”

Section: The Role Of Syngap In Induction Of Ltpmentioning

confidence: 99%

“…This result supports the hypothesis that synGAP acts as a placeholder by occupying PDZ domains “slots” on PSD-95. The effects of phosphorylation on affinity of synGAP for PDZ domains of PSD-95 further suggest that the placeholder function is regulated by activation of NMDARs [37]. …”

Section: The Role Of Syngap In Induction Of Ltpmentioning

confidence: 99%

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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“…synGAP, a dual Ras and Rap GTPase Activating Protein (GAP), is unusually highly concentrated in the PSD of excitatory synapses [2][3][4]. It binds tightly to the PDZ domains of PSD-95 [2,5] which serves to position it in close proximity to NMDA-type and AMPA-type glutamate receptors (NMDARs and AMPARs, respectively), and allows it to regulate the composition of the PSD by restricting binding of other proteins to PSD-95 [6].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases

Walkup

Sweredoski

Graham

et al. 2018

Biochemical and Biophysical Research Communications

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SynGAP is a Ras and Rap GTPase-activating protein (GAP) found in high concentration in the postsynaptic density (PSD) fraction from mammalian forebrain where it binds to PDZ domains of PSD-95. Phosphorylation of pure recombinant synGAP by Ca/calmodulin-dependent protein kinase II (CaMKII) shifts the balance of synGAP's GAP activity toward inactivation of Rap1; whereas phosphorylation by cyclin-dependent kinase 5 (CDK5) has the opposite effect, shifting the balance toward inactivation of HRas. These shifts in balance contribute to regulation of the numbers of surface AMPA receptors, which rise during synaptic potentiation (CaMKII) and fall during synaptic scaling (CDK5). Polo-like kinase 2 (Plk2/SNK), like CDK5, contributes to synaptic scaling. These two kinases act in concert to reduce the number of surface AMPA receptors following elevated neuronal activity by tagging spine-associated RapGAP protein (SPAR) for degradation, thus raising the level of activated Rap. Here we show that Plk2 also phosphorylates and regulates synGAP. Phosphorylation of synGAP by Plk2 stimulates its GAP activity toward HRas by 65%, and toward Rap1 by 16%. Simultaneous phosphorylation of synGAP by Plk2 and CDK5 at distinct sites produces an additive increase in GAP activity toward HRas (∼230%) and a smaller, non-additive increase in activity toward Rap1 (∼15%). Dual phosphorylation also produces an increase in GAP activity toward Rap2 (∼40-50%), an effect not produced by either kinase alone. As we previously observed for CDK5, addition of Ca/CaM causes a substrate-directed doubling of the rate and stoichiometry of phosphorylation of synGAP by Plk2, targeting residues also phosphorylated by CaMKII. In summary, phosphorylation by Plk2, like CDK5, shifts the ratio of GAP activity of synGAP to produce a greater decrease in active Ras than in active Rap, which would produce a shift toward a decrease in the number of surface AMPA receptors in neuronal dendrites.

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A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

Cited by 64 publications

References 72 publications

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

Biochemistry and neuroscience: the twain need to meet

Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases

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A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

Cited by 64 publications

References 72 publications

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca 2+ /CaMKII signaling

Biochemistry and neuroscience: the twain need to meet

Phosphorylation of synaptic GTPase-activating protein (synGAP) by polo-like kinase (Plk2) alters the ratio of its GAP activity toward HRas, Rap1 and Rap2 GTPases

Contact Info

Product

Resources

About

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling

Postsynaptic localization and regulation of AMPA receptors and Cav1.2 by β2 adrenergic receptor/PKA and Ca ²⁺ /CaMKII signaling