Ubiquitination of Metabotropic Glutamate Receptors and Associated Synaptic Proteins In Vitro and In Vivo.

Abstract

Metabotropic glutamate (mGlu) receptors are a family of G protein-coupled receptors. These receptors are widely distributed in the brain and are critical for the modulation of synaptic transmission and plasticity. Emerging evidence shows that mGlu receptors themselves are subject to a dynamic posttranslational modification involving protein ubiquitination. Postsynaptic group I mGlu receptors (mGlu1/5) undergo constitutive ubiquitination at lysine sites on their intracellular domains in heterologous cells and neurons. In particular, ligand stimulation triggers rapid ubiquitination of group I receptors to confer a negative feedback regulation. Like mGlu1/5, presynaptic mGlu7 receptors are ubiquitinated by a specific E3 ubiquitin ligase. Robust ubiquitination is also seen in a number of existing synaptic proteins closely associated with mGlu activity, including Homer1a, the activity-regulated cytoskeleton-associated protein Arc/Arg3.1, and the protein interacting with C-kinase 1. Ubiquitination of mGlu receptors targets the receptors to degradation via the proteasome-dependent or -independent pathway or plays nondegradative roles in the regulation of distinct cellular processes such as endocytic trafficking, protein-protein interactions, and mGlu receptor signaling.