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Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses

Nature Neuroscience volume 8, pages 768–775 (2005)Cite this article

Abstract

At many excitatory central synapses, activity produces a lasting change in the synaptic response by modifying postsynaptic AMPA receptors (AMPARs). Although much is known about proteins involved in the trafficking of Ca2+-impermeable (GluR2-containing) AMPARs, little is known about protein partners that regulate subunit trafficking and plasticity of Ca2+-permeable (GluR2-lacking) AMPARs. At cerebellar parallel fiber–stellate cell synapses, activity triggers a novel type of plasticity: Ca2+ influx through GluR2-lacking synaptic AMPARs drives incorporation of GluR2-containing AMPARs, generating rapid, lasting changes in excitatory postsynaptic current properties. Here we examine how glutamate receptor interacting protein (GRIP, also known as AMPAR binding protein or ABP) and protein interacting with C-kinase-1 (PICK) regulate subunit trafficking and plasticity. We find that repetitive synaptic activity triggers loss of synaptic GluR2-lacking AMPARs by selectively disrupting their interaction with GRIP and that PICK drives activity-dependent delivery of GluR2-containing receptors. This dynamic regulation of AMPARs provides a feedback mechanism for controlling Ca2+permeability of synaptic receptors.

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Figure 1: PICK is not involved in the maintenance of synaptic AMPA receptors in stellate cells.
Figure 2: Pep2-AVKI inhibited the activity-induced increase in the amplitude of EPSCs at +40 mV.
Figure 3: Effect of pep2m and control scrambled peptide (pep2s) on the activity-dependent change in EPSC amplitude, and current-voltage relationships.
Figure 4: Single-channel currents recorded from outside-out patches excised from the soma of stellate cells.
Figure 5: Pep2-SVKI reduced the amplitude of synaptic currents.
Figure 6: Activity-dependent reduction in EPSC amplitude at −60 mV was greater with pep2-SVKI than with pep2-AVKI.

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Acknowledgements

We thank S. Mok and C. Gebhardt for helpful discussions. This work was supported by a Wellcome Trust Programme Grant and a Royal Society-Wolfson Research Award to S.G.C.-C., and a US National Science Foundation grant to S.J.L. S.J.L. received a Wellcome Trust Travelling Fellowship.

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Authors and Affiliations

  1. Department of Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK

    Siqiong June Liu & Stuart G Cull-Candy

  2. Department of Biology, Penn State University, State College, 16801, Pennsylvania, USA

    Siqiong June Liu

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Correspondence to Siqiong June Liu or Stuart G Cull-Candy.

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Supplementary Fig. 1

Proposed model for activity-dependent trafficking of synaptic AMPA receptor subtypes in stellate cells. (PDF 34 kb)

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Liu, S., Cull-Candy, S. Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses. Nat Neurosci 8, 768–775 (2005). https://doi.org/10.1038/nn1468

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