SUPERSTOCKTrafficking of neurotransmitter receptors and ion channels contributes to the regulation of synaptic function, and is thought to have a key role in synaptic plasticity. Both phosphorylation and ubiquitylation have been shown to trigger trafficking of synaptic proteins. In a new study, Martin & Nishimune et al. reveal a role for another post-translational modification, sumoylation, in kainate receptor (KAR) trafficking.
Activation of KARs leads to their internalization through endocytosis, but how this is controlled is currently unknown. Sumoylation, the covalent binding of SUMO (small ubiquitin-related modifier) proteins (SUMO1, 2 and 3) to target proteins, regulates the function of a range of nuclear and cell membrane proteins, suggesting that this process could contribute to KAR trafficking. The authors found evidence of sumoylation of GluR6, a KAR subunit, in cultured rat hippocampal neurons and brain extracts. Furthermore, they showed that sumoylation of GluR6 was increased following stimulation with glutamate or kainate, but not NMDA (N-methyl-D-aspartate).
To examine the role of sumoylation in KAR internalization, the authors expressed a SUMO inhibitor, SENP1, in the neurons. This inhibited kainate-triggered endocytosis of GluR6, indicating that binding of SUMO, in combination with receptor activation, is essential for GluR6 internalization.
The authors showed that SUMO-mediated GluR6 trafficking can dramatically alter synaptic function: infusion of SUMO1 into hippocampal CA3 neurons in brain slices decreased the size of KAR-mediated evoked excitatory postsynaptic currents, whereas infusion of SENP1 increased these currents.
Previous work has shown that sumoylation can modulate neuronal excitability by regulating ion channel opening. This study indicates that sumoylation may also alter synaptic function by contributing to neurotransmitter receptor trafficking. Because NMDA-evoked endocytosis does not involve sumoylation, multiple pathways probably underlie GluR6 endocytosis. The authors suggest that downregulation of KARs, mediated via sumoylation, might help hippocampal neurons resist excitotoxicity. However, we still do not know the factors that link sumoylation to receptor activation, or those by which sumoylation contributes to receptor internalization. Likewise, whether, and under what circumstances, sumoylation of GluR6 contributes to synaptic plasticity remains to be determined.