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

Overview

Journal PLoS Comput Biol

Specialty Biology

Date 2016 Jan 26

PMID 26807999

Citations 8

Authors

Andrew R Gallimore

A Radu Aricescu

Michisuke Yuzaki

Radu Calinescu

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Alves R, Antunes F, Salvador A . Tools for kinetic modeling of biochemical networks. Nat Biotechnol. 2006; 24(6):667-72. DOI: 10.1038/nbt0606-667. View

Beretta F, Sala C, Saglietti L, Hirling H, Sheng M, Passafaro M . NSF interaction is important for direct insertion of GluR2 at synaptic sites. Mol Cell Neurosci. 2005; 28(4):650-60. DOI: 10.1016/j.mcn.2004.11.008. View

Ito M . The molecular organization of cerebellar long-term depression. Nat Rev Neurosci. 2002; 3(11):896-902. DOI: 10.1038/nrn962. View

Manninen T, Makiraatikka E, Ylipaa A, Pettinen A, Leinonen K, Linne M . Discrete stochastic simulation of cell signaling: comparison of computational tools. Conf Proc IEEE Eng Med Biol Soc. 2007; 2006:2013-6. DOI: 10.1109/IEMBS.2006.260023. View

Finch E, Tanaka K, Augustine G . Calcium as a trigger for cerebellar long-term synaptic depression. Cerebellum. 2011; 11(3):706-17. DOI: 10.1007/s12311-011-0314-x. View

Beattie E, Carroll R, Yu X, Morishita W, Yasuda H, von Zastrow M . Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat Neurosci. 2000; 3(12):1291-300. DOI: 10.1038/81823. View

Launey T, Endo S, Sakai R, Harano J, Ito M . Protein phosphatase 2A inhibition induces cerebellar long-term depression and declustering of synaptic AMPA receptor. Proc Natl Acad Sci U S A. 2003; 101(2):676-81. PMC: 327207. DOI: 10.1073/pnas.0302914101. View

Endo S, Suzuki M, Sumi M, Nairn A, Morita R, Yamakawa K . Molecular identification of human G-substrate, a possible downstream component of the cGMP-dependent protein kinase cascade in cerebellar Purkinje cells. Proc Natl Acad Sci U S A. 1999; 96(5):2467-72. PMC: 26808. DOI: 10.1073/pnas.96.5.2467. View

Manninen T, Hituri K, Hellgren Kotaleski J, Blackwell K, Linne M . Postsynaptic signal transduction models for long-term potentiation and depression. Front Comput Neurosci. 2010; 4:152. PMC: 3006457. DOI: 10.3389/fncom.2010.00152. View

10.

Kohda K, Kakegawa W, Matsuda S, Nakagami R, Kakiya N, Yuzaki M . The extreme C-terminus of GluRdelta2 is essential for induction of long-term depression in cerebellar slices. Eur J Neurosci. 2007; 25(5):1357-62. DOI: 10.1111/j.1460-9568.2007.05412.x. View

11.

Osten P, Khatri L, Perez J, Kohr G, Giese G, Daly C . Mutagenesis reveals a role for ABP/GRIP binding to GluR2 in synaptic surface accumulation of the AMPA receptor. Neuron. 2000; 27(2):313-25. DOI: 10.1016/s0896-6273(00)00039-8. View

12.

Matsuo N, Reijmers L, Mayford M . Spine-type-specific recruitment of newly synthesized AMPA receptors with learning. Science. 2008; 319(5866):1104-7. PMC: 2692967. DOI: 10.1126/science.1149967. View

13.

Hironaka K, Umemori H, Tezuka T, Mishina M, Yamamoto T . The protein-tyrosine phosphatase PTPMEG interacts with glutamate receptor delta 2 and epsilon subunits. J Biol Chem. 2000; 275(21):16167-73. DOI: 10.1074/jbc.M909302199. View

14.

Sanz-Clemente A, Matta J, Isaac J, Roche K . Casein kinase 2 regulates the NR2 subunit composition of synaptic NMDA receptors. Neuron. 2010; 67(6):984-96. PMC: 2947143. DOI: 10.1016/j.neuron.2010.08.011. View

15.

Blanpied T, Scott D, Ehlers M . Dynamics and regulation of clathrin coats at specialized endocytic zones of dendrites and spines. Neuron. 2002; 36(3):435-49. DOI: 10.1016/s0896-6273(02)00979-0. View

16.

Boxall A, Lancaster B, Garthwaite J . Tyrosine kinase is required for long-term depression in the cerebellum. Neuron. 1996; 16(4):805-13. DOI: 10.1016/s0896-6273(00)80100-2. View

17.

Tanaka K, Khiroug L, Santamaria F, Doi T, Ogasawara H, Ellis-Davies G . Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator. Neuron. 2007; 54(5):787-800. DOI: 10.1016/j.neuron.2007.05.014. View

18.

Xia J, Chung H, Wihler C, Huganir R, Linden D . Cerebellar long-term depression requires PKC-regulated interactions between GluR2/3 and PDZ domain-containing proteins. Neuron. 2001; 28(2):499-510. DOI: 10.1016/s0896-6273(00)00128-8. View

19.

Steinberg J, Huganir R, Linden D . N-ethylmaleimide-sensitive factor is required for the synaptic incorporation and removal of AMPA receptors during cerebellar long-term depression. Proc Natl Acad Sci U S A. 2004; 101(52):18212-6. PMC: 539805. DOI: 10.1073/pnas.0408278102. View

20.

Tang Q, Tan L, Yang X, Shen Q, Huang X, Wang G . Willed-movement training reduces motor deficits and induces a PICK1-dependent LTD in rats subjected to focal cerebral ischemia. Behav Brain Res. 2013; 256:481-7. DOI: 10.1016/j.bbr.2013.08.039. View