Ubiquitination of Neurotransmitter Receptors and Postsynaptic Scaffolding Proteins

Figure 4

(a) GABAergic ubiquitination. The specific E3 ligase for GABARs has not been identified, although the ubiquitin-like protein Plic-1, which does not function for ubiquitination, directly interacts with GABA_ARs to affect insertion. It stabilizes polyubiquitinated GABA_ARs in the ER to limit ERAD and promote GABA_AR surface expression. Unassembled GABAR subunits in the ER are usually ubiquitinated and targeted to the proteasome. Although the proteasome plays a large role in GABA_AR trafficking, the lysosome also mediates GABA_AR degradation by ubiquitinating a motif in intracellular domain of the γ2 subunit. (b) Cholinergic synapses. In the cholinergic synapse, the E3 ligases remain unidentified although it is known that ubiquitination of the α3, β2, and β4 nAChR subunits is required for degradation. (c) Glycinergic synapses. In glycinergic synapses, extensive ubiquitination to the α1 subunit of GlyR prior to internalization has been observed in Xenopus oocytes though this has not been repeated in a mammalian system. However, it has recently been shown that the glycine transporter GLYT1 1b subunit undergoes ubiquitination at lysine 619, causing rapid endocytosis. (d) Dopaminergic synapses. In dopaminergic synapses, KLHL12 acts as an adaptor to the E3 ligase Cul3 to promote polyubiquitination of both immature ER-associated and mature membrane-associated forms of the D4 receptor though there is apparently neither proteasomal nor lysosomal degradation observed. The D2 receptor subtype is known to be monoubiquitinated, although possible polyubiquitinated forms may also exist. An E3 ligase has yet to be identified.