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

PLoS Computational Biology
Andrew R GallimoreRadu Calinescu

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 int...Continue Reading

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Citations

Apr 25, 2017·Integrative Biology : Quantitative Biosciences From Nano to Macro·Jared C Weddell, Princess I Imoukhuede
Jan 24, 2017·Trends in Neurosciences·Michisuke Yuzaki, A Radu Aricescu
Jul 22, 2019·The Journal of General Physiology·Miriam BellPadmini Rangamani
Mar 14, 2019·Frontiers in Cellular Neuroscience·Taegon Kim, Keiko Tanaka-Yamamoto
Dec 20, 2018·Frontiers in Molecular Neuroscience·C G Zamora Chimal, Erik De Schutter
Feb 22, 2017·Frontiers in Molecular Neuroscience·Iain HepburnErik De Schutter

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