Routes, destinations and delays: recent advances in AMPA receptor trafficking

Abstract

Postsynaptic AMPA-type glutamate receptors (AMPARs) mediate most fast excitatory synaptic transmission and are crucial for many aspects of brain function, including learning, memory and cognition. The number, synaptic localization and subunit composition of synaptic AMPARs are tightly regulated by network activity and by the history of activity at individual synapses. Furthermore, aberrant AMPAR trafficking is implicated in neurodegenerative diseases. AMPARs therefore represent a prime target for drug development and the mechanisms that control their synaptic delivery, retention and removal are the subject of extensive research. Here, we review recent findings that have provided new insights into AMPAR trafficking and that might lead to the development of novel therapeutic strategies.

Figure 1

Molecular processes involved in directing AMPAR trafficking in LTP. (a) Presynaptic glutamate release activates NMDARs, leading to Ca²⁺ influx in the postsynaptic cell. (b) Calcium activates CaMKII, leading to the phosphorylation of GluA1. (c) Receptors containing phosphorylated GluA1 are coupled via the Rab11 adaptor complex to the Ca²⁺-activated motor protein MyoVa, which transports them over a short range along actin filaments from dendritic shafts to the spine head. (d) MyoVb is activated by Ca²⁺ and transports AMPAR along the actin cytoskeleton to sites of exocytosis. (e) PKC phosphorylation of GluA1 at S816 and S818 increases its affinity for the cytoskeletal adaptor protein 4.1N, which is required for membrane insertion and links AMPARs to the actin cytoskeleton. (f) PKA phosphorylation of GluA1 at S845 leads to AMPAR insertion at extrasynaptic and perisynaptic sites, ready for delivery to synapses. (g) Sites of exocytosis are enriched in syntaxin 4, which mediates membrane fusion events. (h) Diffusive Ras-–ERK signaling is required for exocytosis on dendrites and spines up to 3 μM from the synaptic site of potentiation. (i) PKC phosphorylation of CP-AMPARs at perisynaptic sites leads to their transfer to synaptic sites. These are later replaced by edited GluA2-containing receptors. (j) Phosphorylation of stargazin (γ2) by CaMKII. (k) The interaction between phosphorylated stargazin and PSD-95 traps AMPARs at synapses. (l) PKMζ maintains AMPARs at synapses by downregulating GluA2-containing receptor internalization, possibly via NSF-mediated disassembly of GluA2/–PICK1 complexes.

Figure 2

Mechanisms of AMPARs endocytosis. Endocytosis in the spine might be localized to the clathrin-enriched endocytic zones adjacent to the PSD, shown here in green. The left spine depicts mechanisms involved in NMDAR-dependent endocytosis, whereas the right spine represents endocytosis not involving NMDAR activation, namely basal conditions, mGluR activation and synaptic scaling. (a) Phosphorylation of GluA2 at Tyr876 regulates its binding to BRAG2, which in turn activates the small GTPase Arf6 to internalize AMPARs on induction of both NMDAR- and mGluR-dependent LTD. (b) Ubiquitination by the E3 ligase Mdm2 and the subsequent proteasomal degradation of PSD-95 might be required for NMDAR-dependent endocytosis of AMPARs, although whether PSD-95 itself and/or an intermediate is polyubiquitinated for degradation remains to be further investigated. (c) Interactions between the synaptic anchoring protein, AKAP150 and calcineurin are required for NMDAR-dependent endocytosis of AMPARs. The binding of AKAP150 to PSD-95 is also required for NMDAR-dependent LTD. AKAP150 is involved in the localization of PKA and other proteins involved in the synaptic trafficking of AMPARs. (d) NMDAR stimulation activates RalA and dephosphorylates the endocytic adaptor, RalBP1. (e) RalA and PSD-95 target dephosphorylated RalBP1 to sites of endocytosis. (f) PICK1 interacts with the GluA2 subunit, promoting phosphorylation at Ser880 by PKC, leading to AMPAR endocytosis during NMDAR-LTD (however, alternative intracellular retention roles for PICK1 have also been proposed, as discussed in the main text). (g) PICK1 binds the Arp2/3 complex, an actin-nucleating protein, inhibiting its activity. This leads to a net reduction in the actin polymerization rate in treadmilling actin near the membrane, reducing membrane tension, which might promote AMPAR internalization subsequent to NMDAR stimulation [note, as for (f)]. (h) Arc/Arg3.1 interacts with components of endocytic machinery, such as endophilin and dynamin, to regulate constitutive endocytosis as well as internalization associated with mGluR activation and synaptic scaling. (i) The postsynaptic scaffold/adaptor protein, Homer, interacts with dynamin, coupling endocytic zones to the PSD. Loss of the Homer/–dynamin interaction results in loss of clathrin and endocytosis at the PSD. (j) Eph4 activation leads to the ubiquitination and degradation of GluA1-containing receptors during homeostatic plasticity.