Molecular mechanisms and synaptic functions of kainate receptor SUMOylation

Efficient communication between neurones at synapses is required for proper brain function. This communication uses chemical transmitters and relies on the presence of receptor proteins at the synapse surface. A key feature of this system is that the number of receptors changes depending on the activity at the synapse. We have found that for one type of receptor called the kainate receptor, binding of the transmitter leads to attachment of a small protein called SUMO and this results in the receptor being removed from the surface into the cell (where it can no longer function) by a mechanism called endocytosis. Preventing SUMO attachment to kainate receptors blocks endocytosis. We go on to demonstrate that this process regulates communication between neurones. This is significant because kainate receptors regulate the general excitability of neurones and synaptic transmission and their dysfunction has been implicated in diseases such as epilepsy and Huntington's disease. In addition, we show that in addition to the receptor we have characterised, there are many other proteins present at synapses that undergo similar addition of SUMO. The aim of this proposal is to go on to work out some of the details of how this process works. Specifically we want to find out what change in the receptor allows it to bind SUMO and what molecular changes take place once the receptor is SUMOylated. We believe these experiments will have very important implications for understanding how synapses function. Furthermore, once we shed light on how kainate receptors are handled in normal cells we can then gain insight into what happens in injured or diseased cells and try to formulate strategies to compensate for or repair the problems.

Kainate receptors (KARs) play crucial roles in the regulation of both excitatory and inhibitory neurotransmission. Their dysfunction has been proposed to underlie or contribute to many conditions that have a major impact on the quality and length of human life associated with profound economic and social consequences for society as a whole. Protein SUMOylation has important roles in the regulation of nuclear function. Far less well investigated are the targets and roles of SUMO modification outside the nucleus. In a paper in press at Nature, we have shown that SUMOylation of the GluR6a KAR subunit following agonist activation evokes kainate receptor endocytosis and modulation of synaptic transmission. The specific implications of our observations are that regulation of kainate receptors by SUMOylation will be involved in synaptic plasticity and neuronal excitability. In a wider context, our findings raise the prospect that protein SUMOylation, similar to other posttranslational modifications such as phosphorylation and ubiquitination, may be of fundamental importance in controlling the interactions and functions of synaptic target proteins. The aim of this proposal is to elucidate the upstream and downstream events and processes that lead to and result from GluR6 SUMOylation. We intend to explore the roles of phosphorylation as a potential trigger for SUMOylation and the effects SUMOylation has on PDZ interactions and protein complex formation. In addition, we aim to identify proteins specifically involved in the SUMOylation-dependent endocytic pathway and investigate the role of GluR6 SUMOylation in certain types of synaptic plasticity. We believe that these are novel and important issues that we are in a unique position to address.