Regulation of AMPA receptor surface diffusion by PSD-95 slots
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)
- et al.
A three-step model for the synaptic recruitment of AMPA receptors
Mol Cell Neurosci
(2011) - et al.
Bidirectional redistribution of AMPA but not NMDA receptors after perforant path simulation in the adult rat hippocampus in vivo
Hippocampus
(2006) - et al.
LTP mechanisms: from silence to four-lane traffic
Curr Opin Neurobiol
(2000) - et al.
AMPA receptor trafficking at excitatory synapses
Neuron
(2003) - et al.
PDZ domains in synapse assembly and signalling
Trends Cell Biol
(2000) - et al.
Receptor trafficking and synaptic plasticity
Nat Rev Neurosci
(2004) - et al.
Synaptic SAP97 isoforms regulate AMPA receptor dynamics and access to presynaptic glutamate
J Neurosci
(2009) - et al.
Hippocampal LTD expression involves a pool of AMPARs regulated by the NSF–GluR2 interaction
Neuron
(1999) - et al.
Interaction of the N-terminal domain of the AMPA receptor GluR4 subunit with the neuronal pentraxin NP1 mediates GluR4 synaptic recruitment
Neuron
(2007) - et al.
Activity-independent and subunit-specific recruitment of functional AMPA receptors at neurexin/neuroligin contacts
Proc Natl Acad Sci USA
(2008)
Neurexin-neuroligin adhesions capture surface-diffusing AMPA receptors through PSD-95 scaffolds
J Neurosci
Auxiliary subunits assist AMPA-type glutamate receptors
Science
M-422: Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms
Nature
Interaction of transmembrane AMPA receptor regulatory proteins with multiple membrane associated guanylate kinases
Neuropharmacology
The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits
Neuron
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor
Nature
Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions
Neuron
Self-directed assembly and clustering of the cytoplasmic domains of inwardly rectifying Kir2.1 potassium channels on association with PSD-95
Biochimt Biophys Acta
Different domains of the AMPA receptor direct stargazin-mediated trafficking and stargazin-mediated modulation of kinetics
J Biol Chem
Interaction between SAP97 and PSD-95, two Maguk proteins involved in synaptic trafficking of AMPA receptors
J Biol Chem
Lipid- and protein-mediated multimerization of PSD-95: implications for receptor clustering and assembly of synaptic protein networks
J Cell Sci
Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs
Neuron
Synaptic strength regulated by palmitate cycling on PSD-95
Cell
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
An intramolecular interaction between Src homology 3 domain and guanylate kinase-like domain required for channel clustering by postsynaptic density-95/SAP90
J Neurosci
Supramodular structure and synergistic target binding of the N-terminal tandem PDZ domains of PSD-95
J Mol Biol
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
Domain orientation in the N-Terminal PDZ tandem from PSD-95 is maintained in the full-length protein
Structure
Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins
Proc Natl Acad Sci USA
Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity
J Neurosci
Synapse-specific and developmentally regulated targeting of AMPA receptors by a family of MAGUK scaffolding proteins
Neuron
Postsynaptic density-95 mimics and occludes hippocampal long-term potentiation and enhances long-term depression
J Neurosci
PIP3 controls synaptic function by maintaining AMPA receptor clustering at the postsynaptic membrane
Nat Neurosci
Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity
Neuron
M-447: Bidirectional synaptic plasticity regulated by phosphorylation of stargazin-like TARPs
Neuron
Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer
J Neurosci
The stress hormone corticosterone conditions AMPARs surface trafficking and synaptic potentiation
Nat Neurosci
Synaptic plasticity and memory: an evaluation of the hypothesis
Annu Rev Neurosci
Learning induces long-term potentiation in the hippocampus
Science
Involvement of the CA3-CA1 synapse in the acquisition of associative learning in behaving mice
J Neurosci
The cell biology of synaptic plasticity: AMPA receptor trafficking
Annu Rev Cell Dev Biol
Regulation of AMPA receptor lateral movements
Nature
Direct imaging of lateral movements of AMPA receptors inside synapses
Embo J
The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking
Neuron
Surface mobility of postsynaptic AMPARs tunes synaptic transmission
Science
Trafficking of AMPA receptors at plasma membranes of hippocampal neurons
J Neurosci
AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis
Neuron
Endocytic trafficking and recycling maintain a pool of mobile surface AMPA receptors required for synaptic potentiation
Neuron
Cited by (168)
Synapse organizers as molecular codes for synaptic plasticity
2023, Trends in NeurosciencesSynaptic logistics: Competing over shared resources
2023, Molecular and Cellular Neuroscience