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. Author manuscript; available in PMC: 2012 Mar 28.
Published in final edited form as: Trends Neurosci. 2011 Mar 21;34(5):258–268. doi: 10.1016/j.tins.2011.02.004

Figure 2.

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.