Proper neuronal function requires precise temporal and spatial regulation of protein levels, and this is largely occurs via control over the translation of mRNAs into new proteins and the degradation of existing proteins by the ubiquitin-proteasome system (UPS). Studies using pharmacological inhibitors of protein synthesis and the UPS have indicated that these processes are critical for long-term synaptic plasticity and memory consolidation, and regulation of these processes is likely involved in the plasticity of brain reward systems that mediates the development of addiction. Emerging evidence suggests that stabilization of long-term plasticity requires gene-specific, rather than global, translational control and coordination or balance of protein synthesis and degradation processes. The mechanisms by which this occurs, the specific changes in protein expression that result, and the consequences of these processes for drug-mediated behavior are critical issues that this proposal seeks to elucidate by investigating the role and regulation of eukaryotic elongation factor-2 kinase, a Ca2????dependent protein kinase that exerts translational control by phosphorylating eukaryotic elongation factor-2 (eEF-2) and inhibiting translation at the elongation step. Previous studies and preliminary data suggest that EF2K is a central mediator both of gene-specific translation and the coordination of protein synthesis and degradation, although the mechanisms and consequences of these functions remain to be elucidated. To this end, the proposed research will characterize the mechanisms by which EF2K is targeted for UPS-mediated degradation in response to stimulation, the specific regulation that EF2K exerts on patterns of protein expression, and the role of EF2K in locomotor sensitization to cocaine. These studies will advance understanding of the role of gene-specific modes of translation and coordination of protein synthesis and degradation, as well as the mechanisms of plasticity mediated by drugs of abuse, potentially enabling the development of novel therapeutics.
The goal of this proposal is to characterize the function of gene-specific translational control and coordination of protein synthesis and degradation in cocaine-mediated behavior, the mechanisms by which these processes occur, and their specific consequences for patterns of protein expression. The long-term changes in neural reward circuitry that underlie addiction are thought to engage these molecular processes, and by characterizing them in detail, novel approaches to the treatment of addiction may be developed.
|Wiseman, Shari L; Shimizu, Yoshio; Palfrey, Clive et al. (2013) Proteasomal degradation of eukaryotic elongation factor-2 kinase (EF2K) is regulated by cAMP-PKA signaling and the SCF?TRCP ubiquitin E3 ligase. J Biol Chem 288:17803-11|