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In the mammalian central nervous system, glutamate receptors are the most abundant excitatory neurotransmitter receptors. The density of receptors at synapses greatly impacts signal strength, and synaptic accumulation of glutamate receptors is highly regulated. Post-translational modifications, such as ubiquitination and SUMOylation, are known to play key roles in regulating protein turnover and thereby protein expression at synapses. Conjugation of polyubiquitin tags to specific lysine residues on target proteins signals them for degradation whereas monoubiquitination is a signal for internalization. Many enzymes are involved in ubiquitin pathways; of them, the group of E3 ligases containing a RING domain is the most abundant. The membrane spanning and membrane bound E3 ligases regulate the ubiquitin conjugation of membrane proteins. Recently our lab has screened endosomal transmembane E3 ligases for effects on glutamate receptor surface expression. We found that that loss of function mutations in two of these E3 ubiqutin ligases, RNF 112 and RNF 167, increases the relative surface expression of specific glutamate receptors, including the glutamate receptor subunits GluR2 and GluR6.

The goal of my project is to both develop tools that will allow for more investigation into the E3 ligase/glutamate receptor relationship and to study the neuronal expression and trafficking of RNF 167 and RNF 112. I have been developing an antibody against RNF 167, as there are currently no antibodies available. I initially selected ideal antigenic regions and I am now making fusion proteins of these regions. Following purification, they will be injected into rabbits to produce antibodies. The second part of my project takes advantage of commercially available antibodies to other E3 ubiquitin ligases of interest including RNF 112. I have been examining the subcellular localization of RNF112 in neurons by immunocytochemical analysis and a potential interaction between RNF 112 and glutamate subunits through immunoprecipitation. In addition I have been examining the effects of these E3 ligases on glutamate receptors trafficking in neurons by immunocytochemical analysis. These studies will allow us to define the precise role for these E3 ligases in regulating glutamate receptor trafficking and ultimately excitatory synaptic transmission.

Last updated November 16, 2007