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A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

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A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression. / Gallimore, Andrew Robert; Aricescu, A. Radu; Yuzaki, Michisuke; Calinescu, Radu.

In: PLoS Computational Biology, Vol. 12, No. 1, 1004664, 25.01.2016.

Research output: Contribution to journalArticle

Harvard

Gallimore, AR, Aricescu, AR, Yuzaki, M & Calinescu, R 2016, 'A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression', PLoS Computational Biology, vol. 12, no. 1, 1004664. https://doi.org/10.1371/journal.pcbi.1004664

APA

Gallimore, A. R., Aricescu, A. R., Yuzaki, M., & Calinescu, R. (2016). A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression. PLoS Computational Biology, 12(1), [1004664]. https://doi.org/10.1371/journal.pcbi.1004664

Vancouver

Gallimore AR, Aricescu AR, Yuzaki M, Calinescu R. A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression. PLoS Computational Biology. 2016 Jan 25;12(1). 1004664. https://doi.org/10.1371/journal.pcbi.1004664

Author

Gallimore, Andrew Robert ; Aricescu, A. Radu ; Yuzaki, Michisuke ; Calinescu, Radu. / A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression. In: PLoS Computational Biology. 2016 ; Vol. 12, No. 1.

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@article{af79bc4646ae47e79fe9cca0e6bc9fba,
title = "A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression",
abstract = "The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.",
author = "Gallimore, {Andrew Robert} and Aricescu, {A. Radu} and Michisuke Yuzaki and Radu Calinescu",
note = "{\circledC} The Authors 2015. This content is made available by the publisher under a Creative Commons Attribution Licence. This means that a user may copy, distribute and display the resource providing that they give credit. Users must adhere to the terms of the licence.",
year = "2016",
month = "1",
day = "25",
doi = "10.1371/journal.pcbi.1004664",
language = "English",
volume = "12",
journal = "PLoS Computational Biology",
issn = "1553-7358",
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}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - A Computational Model for the AMPA Receptor Phosphorylation Master Switch Regulating Cerebellar Long-Term Depression

AU - Gallimore, Andrew Robert

AU - Aricescu, A. Radu

AU - Yuzaki, Michisuke

AU - Calinescu, Radu

N1 - © The Authors 2015. This content is made available by the publisher under a Creative Commons Attribution Licence. This means that a user may copy, distribute and display the resource providing that they give credit. Users must adhere to the terms of the licence.

PY - 2016/1/25

Y1 - 2016/1/25

N2 - The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.

AB - The expression of long-term depression (LTD) in cerebellar Purkinje cells results from the internalisation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) from the postsynaptic membrane. This process is regulated by a complex signalling pathway involving sustained protein kinase C (PKC) activation, inhibition of serine/threonine phosphatase, and an active protein tyrosine phosphatase, PTPMEG. In addition, two AMPAR-interacting proteins–glutamate receptor-interacting protein (GRIP) and protein interacting with C kinase 1 (PICK1)–regulate the availability of AMPARs for trafficking between the postsynaptic membrane and the endosome. Here we present a new computational model of these overlapping signalling pathways. The model reveals how PTPMEG cooperates with PKC to drive LTD expression by facilitating the effect of PKC on the dissociation of AMPARs from GRIP and thus their availability for trafficking. Model simulations show that LTD expression is increased by serine/threonine phosphatase inhibition, and negatively regulated by Src-family tyrosine kinase activity, which restricts the dissociation of AMPARs from GRIP under basal conditions. We use the model to expose the dynamic balance between AMPAR internalisation and reinsertion, and the phosphorylation switch responsible for the perturbation of this balance and for the rapid plasticity initiation and regulation. Our model advances the understanding of PF-PC LTD regulation and induction, and provides a validated extensible platform for more detailed studies of this fundamental synaptic process.

U2 - 10.1371/journal.pcbi.1004664

DO - 10.1371/journal.pcbi.1004664

M3 - Article

VL - 12

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-7358

IS - 1

M1 - 1004664

ER -