Figure 3.

Postsynaptic ubiquitination. (a) Postsynaptic density proteins that undergo ubiquitination. PSD-95 is ubiquitinated by Mdm2. It is also monoubiquitinated at multiple sites and may be polyubiquitinated under specific circumstances. SPAR ubiquitination is reliant upon activity-dependent phosphorylation by Plk2 and regulated by the E3 complex SCF^β-TRCP. Stimulation of neuronal activity can also cause TRIM3-mediated ubiquitination of GKAP. GKAP forms a scaffolding complex with Shank and GRIP, which are also ubiquitinated although their specific E3 ligases remain unidentified. PICK1 ubiquitination is mediated by parkin, which monoubiquitinates PICK1 to potentially regulate its downstream effects. (b) Ubiquitinated proteins at glutamatergic synapses in the mammalian system. mGluR1 and mGluR5 can be ubiquitinated by the E3 ligase Siah1A, which binds to a site in the C-terminus of both mGluRs. In mGluR5, Siah1A has been shown to mediate ubiquitination at multiple lysine residues. In the case of KARs, actinofilin acts as a scaffold to bind GluK2-containing KARs to the E3 ligase Cul3. During NMDAR assembly in the ER, glycosylated GluN1 is ubiquitinated by Fbx2, which also can recognize and ubiquitinate GluN2A. Fbx2 can also couple with other cochaperones such as CHIP to regulate GluN2A ubiquitination. GluN2B on the other hand, is localized to the PSD and ubiquitinated by Mib2. The GluA1 subunit of AMPARs has recently been shown to be ubiquitinated by Nedd4-1 primarily at K868. Another member of the Nedd4 family, Nedd4-2, has been shown to ubiquitinate the glial glutamate transporter EAAT2. Another recently identified E3 ligase for GluA1 is APC. As of yet, no E3 ligase has been identified for GluA2.