Regulation of AMPA receptor surface diffusion by PSD-95 slots

https://doi.org/10.1016/j.conb.2011.10.010Get rights and content

Excitatory synaptic transmission is largely mediated by AMPA receptors (AMPARs) present at the postsynaptic density. Recent studies in single molecule tracking of AMPAR has revealed that extrasynaptic AMPARs are highly mobile and thus might serve as a readily available pool for their synaptic recruitment during synaptic plasticity events such as long-term potentiation (LTP). Because this hypothesis relies on the cell's ability to increase the number of diffusional traps or ‘slots’ at synapses during LTP, we will review a number of protein–protein interactions that might impact AMPARs lateral diffusion and thus potentially serve as slots. Recent studies have identified the interaction between the AMPAR–Stargazin complex and PSD-95 as the minimal components of the diffusional trapping slot. We will overview the molecular basis of this critical interaction, its activity-dependent regulation and its potential contribution to LTP.

Highlights

AMPA receptors diffuse in neuronal membranes and are reversibly trapped at synapses. ► AMPAR–Stargazin complex interaction with PSD-95 traps AMPAR at synapses. ► Anchoring of TARP-containing AMPARs involves multivalent PDZ domain interactions. ► Stargazin phosphorylation regulates AMPAR diffusion by regulating binding to PSD-95.

Introduction

Current models of learning and memory propose that neuronal networks store information via modification in synaptic strength, a phenomenon known as synaptic plasticity [1]. Along this line, associative learning can trigger long-term potentiation (LTP) of synaptic transmission in the hippocampus [2, 3]. Because the strength of synaptic transmission is largely dependent on the number of AMPARs anchored at the postsynaptic density (PSD), it is believed that understanding the mechanism of AMPARs trafficking will shed light into the molecular basis of LTP and memory [4]. Taking into consideration recent studies on AMPARs surface dynamics, we had proposed a three-step model for the synaptic recruitment of AMPAR: firstly, intracellular AMPAR-containing vesicles are mobilized to the extra/perisynaptic surface, secondly, AMPARs diffuse laterally to synaptic sites and thirdly AMPARs are diffusionally trapped at the PSD [5]. In this review, we will focus our discussion on the mechanisms underlying the diffusional trapping of AMPARs because it probably corresponds to the rate-limiting step in the synaptic recruitment of AMPAR.

Section snippets

AMPARs surface dynamics during LTP

Using single particle tracking approaches, we have shown that extrasynaptic AMPARs are highly mobile (50–80% mobile fraction) [6••, 7•, 8••]. Importantly, the mobility of extrasynaptic AMPARs is not restricted to the extrasynaptic surface: extrasynaptic AMPARs can enter, scan and exit synapses, the average residence time of mobile AMPARs in synapses being around 2 s. We established that this high mobility serves to facilitate recovery from synaptic depression due to AMPARs desensitization during

Regulation of AMPARs surface trafficking by interacting proteins

AMPARs surface mobility is powered solely by thermal Brownian agitation of molecules. Brownian forces are weak, hence receptor movements are markedly affected by any interaction with immobile or slowly moving molecular structures. AMPARs have been shown to interact with a wide variety of intracellular, transmembrane and extracellular proteins (Table 1). Most of these interactions control the targeting and signaling properties of AMPARs within the postsynaptic membrane [4, 17, 18]. There is now

Molecular details of the TARPs–PSD-95 interaction

Despite overwhelming data indicating the critical aspect of the interaction between the AMPARs–TARP complex and PSD-95 as the main point of regulation of synaptic AMPARs trafficking, the molecular details underlying this complex macromolecular structure yet remains to be precisely defined. Significant progress has been made by resolving the structure of AMPA receptors [48] and by recent structural insights on Stargazin cytoplasmic tail [49]. Likewise, many domains of PSD-95-like proteins have

Regulation of the PSD-95–Stargazin interaction during LTP

Does LTP facilitate the interaction between PSD-95 and Stargazin, and if so, how? One possibility is that LTP occurs simply by the active recruitment of additional PSD-95 ‘slots’, thus promoting the passive trapping of more Stargazin/AMPARs complexes. This scenario is consistent with numerous studies showing that PSD-95 overexpression is sufficient to potentiate synaptic transmission [47•, 76, 77•]. In addition, PSD-95-mediated potentiation occludes LTP, arguing for a shared molecular mechanism

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to the colleagues whose work we were unable to cite owing to space constraints. Research carried out by the authors was supported by grants from the Centre National de la Recherche Scientifique, the Conseil Régional d’Aquitaine, the Ministère de la Recherche, the European research council (nano-dyn-syn) to D.C., the Agence Nationale de la Recherche (ChemTraffic) to D.C. and M.S., the Fondation pour la Recherche Médicale and a marie-curie training grant to P.O.

References (96)

  • M. Mondin et al.

    Neurexin-neuroligin adhesions capture surface-diffusing AMPA receptors through PSD-95 scaffolds

    J Neurosci

    (2011)
  • R.A. Nicoll et al.

    Auxiliary subunits assist AMPA-type glutamate receptors

    Science

    (2006)
  • L. Chen et al.

    M-422: Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms

    Nature

    (2000)
  • S. Dakoji et al.

    Interaction of transmembrane AMPA receptor regulatory proteins with multiple membrane associated guanylate kinases

    Neuropharmacology

    (2003)
  • A.C. Jackson et al.

    The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits

    Neuron

    (2011)
  • A.I. Sobolevsky et al.

    X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor

    Nature

    (2009)
  • T. Nakagawa et al.

    Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions

    Neuron

    (2004)
  • S. Fomina et al.

    Self-directed assembly and clustering of the cytoplasmic domains of inwardly rectifying Kir2.1 potassium channels on association with PSD-95

    Biochimt Biophys Acta

    (2011)
  • M.A. Bedoukian et al.

    Different domains of the AMPA receptor direct stargazin-mediated trafficking and stargazin-mediated modulation of kinetics

    J Biol Chem

    (2006)
  • C. Cai et al.

    Interaction between SAP97 and PSD-95, two Maguk proteins involved in synaptic trafficking of AMPA receptors

    J Biol Chem

    (2006)
  • K.S. Christopherson et al.

    Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks

    J Cell Sci

    (2003)
  • S.E. Craven et al.

    Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs

    Neuron

    (1999)
  • D. El-Husseini Ael et al.

    Synaptic strength regulated by palmitate cycling on PSD-95

    Cell

    (2002)
  • N. Masuko et al.

    Interaction of NE-dlg/SAP102, a neuronal and endocrine tissue-specific membrane-associated guanylate kinase protein, with calmodulin and PSD-95/SAP90. A possible regulatory role in molecular clustering at synaptic sites

    J Biol Chem

    (1999)
  • H. Shin et al.

    An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90

    J Neurosci

    (2000)
  • J.F. Long et al.

    Supramodular structure and synergistic target binding of the N-terminal tandem PDZ domains of PSD-95

    J Mol Biol

    (2003)
  • W. Wang et al.

    Creating conformational entropy by increasing interdomain mobility in ligand binding regulation: a revisit to N-terminal tandem PDZ domains of PSD-95

    J Am Chem Soc

    (2009)
  • J.J. McCann et al.

    Domain orientation in the N-Terminal PDZ tandem from PSD-95 is maintained in the full-length protein

    Structure

    (2011)
  • L. Bard et al.

    Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins

    Proc Natl Acad Sci USA

    (2010)
  • I. Ehrlich et al.

    Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity

    J Neurosci

    (2004)
  • G.M. Elias et al.

    Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins

    Neuron

    (2006)
  • V. Stein et al.

    Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression

    J Neurosci

    (2003)
  • K.L. Arendt et al.

    PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane

    Nat Neurosci

    (2010)
  • P. Steiner et al.

    Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity

    Neuron

    (2008)
  • S. Tomita et al.

    M-447: Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs

    Neuron

    (2005)
  • K. Hashimoto et al.

    Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer

    J Neurosci

    (1999)
  • L. Groc et al.

    The stress hormone corticosterone conditions AMPARs surface trafficking and synaptic potentiation

    Nat Neurosci

    (2008)
  • S.J. Martin et al.

    Synaptic plasticity and memory: an evaluation of the hypothesis

    Annu Rev Neurosci

    (2000)
  • J.R. Whitlock et al.

    Learning induces long-term potentiation in the hippocampus

    Science

    (2006)
  • A. Gruart et al.

    Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice

    J Neurosci

    (2006)
  • J.D. Shepherd et al.

    The cell biology of synaptic plasticity: AMPA receptor trafficking

    Annu Rev Cell Dev Biol

    (2007)
  • A.J. Borgdorff et al.

    Regulation of AMPA receptor lateral movements

    Nature

    (2002)
  • C. Tardin et al.

    Direct imaging of lateral movements of AMPA receptors inside synapses

    Embo J

    (2003)
  • C. Bats et al.

    The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking

    Neuron

    (2007)
  • M. Heine et al.

    Surface mobility of postsynaptic AMPARs tunes synaptic transmission

    Science

    (2008)
  • J.H. Tao-Cheng et al.

    Trafficking of AMPA receptors at plasma membranes of hippocampal neurons

    J Neurosci

    (2011)
  • H. Makino et al.

    AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis

    Neuron

    (2009)
  • E.M. Petrini et al.

    Endocytic trafficking and recycling maintain a pool of mobile surface AMPA receptors required for synaptic potentiation

    Neuron

    (2009)
  • Cited by (168)

    • Synaptic logistics: Competing over shared resources

      2023, Molecular and Cellular Neuroscience
    View all citing articles on Scopus
    View full text