ReviewNeuroscience

Mechanisms of postsynaptic localization of AMPA-type glutamate receptors and their regulation during long-term potentiation

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Science Signaling  01 Jan 2019:
Vol. 12, Issue 562, eaar6889
DOI: 10.1126/scisignal.aar6889

Figures

  • Fig. 1 Structural architecture of AMPARs.

    AMPARs are formed by four subunits, which are conformationally (and functionally) distinct (“pore-proximal” subunits are in gray, and “pore-distal subunits” are in blue). These subunits consist of an extracellular N-terminal domain, the ligand-binding domain, an integral membrane domain, and an intracellular C-terminal domain and form tetrameric receptors (chains A to D). The large extracellular region faces the ER-lumen during receptor biogenesis and ultimately projects into the synaptic cleft. The TARPs interact with the receptor at up to four positions around the transmembrane domain (two nonequivalent positions indicated in red; structure reproduced from the Protein Data Bank: 5WEO).

    CREDIT: ADAPTED BY A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 2 Dendritic AMPAR trafficking.

    AMPARs are synthesized either in the soma (not depicted) or dendritic shaft in the ER. From the dendritic ER, AMPARs traffic through the ER-Golgi intermediate compartment to recycling endosomes, which mediate surface insertion of AMPARs (31). It is unclear where exactly exocytosis occurs, but it is likely either in the dendritic shaft near dendritic spines or in the dendritic spines outside the PSD. AMPARs then move through lateral diffusion to the PSD, where they are trapped by PSD-95 and its homologs through their binding of their three PDZ domains (labeled 1, 2, and 3) to the C termini of TARPs. PSD-95 is anchored at postsynaptic sites by α-actinin. When and where TARPs, which are mostly if not exclusively translated in the soma (31), associate with AMPARs and especially those synthesized in dendrites are unknown. SH3, Src homology 3; GK, guanylate kinase.

    CREDIT: KELLIE HOLOSKI/SCIENCE SIGNALING
  • Fig. 3 Regulation of perisynaptic AMPAR trafficking.

    We propose that norepinephrine (NE) is shuttled by the amino acid transporter OCT3 localized in the plasma membrane from the cell exterior into the cytosol and then by OCT3 localized in recycling endosomes into their lumen. Here, NE stimulates the β2-adrenergic receptor (β2AR) associated with GluA1, which induces PKA activation and phosphorylation of Ser845 in the C terminus of GluA1 (black line originating from AMPAR complex in recycling endosome and perisynaptic space). This phosphorylation event increases surface delivery of AMPARs from recycling endosomes. Lateral diffusion allows AMPARs to reach the PSD, where they are trapped by binding of the C termini of TARPs to PSD-95.

    CREDIT: KELLIE HOLOSKI/SCIENCE SIGNALING
  • Fig. 4 The AMPAR–

    β2-adrenergic receptor signaling complex. The β2-adrenergic receptor binds through its extreme C terminus to the third PDZ domain of PSD-95. In turn, the first two PDZ domains of PSD-95 bind to the C termini of TARPs (red) including γ2 and γ8. Adenylyl cyclase binds through its N terminus to the N terminus of A-kinase–anchoring protein 5 (AKAP5) (also known as AKAP79 in humans, AKAP75 in cow, and AKAP150 in rodents), which binds through its C terminus to PKA. AKAP5 is connected to AMPARs through synapse-associated protein 97 (SAP97), which binds to the C terminus of GluA1, and potentially also through PSD-95. How Gs is linked to the β2-adrenergic receptor–AMPAR complex is unknown but could be through preassociation with the β2-adrenergic receptor.

    CREDIT: KELLIE HOLOSKI/SCIENCE SIGNALING
  • Fig. 5 Regulation of postsynaptic AMPAR trafficking.

    LTP-inducing stimuli trigger the influx of Ca2+ through NMDARs. Ca2+ binds to CaM and stimulates the activity of CaMKII. CaMKII is then recruited to the NMDAR complex by binding to the C terminus of the GluN2B subunit. It subsequently phosphorylates the C termini of TARPs including γ2 and γ8, which may lead to AMPAR trapping at the PSD. Phosphorylation of GluA1 on Ser831 by CaMKII also augments its channel activity.

    CREDIT: KELLIE HOLOSKI/SCIENCE SIGNALING

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