STEP₆₁ is a regulator of mGluR5 expression

Metabotropic glutamate receptor 5 (mGluR5) is a Gq protein-coupled receptor that modulates both excitatory and inhibitory neurotransmission and regulates numerous higher-order neural processes ranging from learning and memory to mood and behavior. Trafficking of mGluR5 to the plasma membrane is critical for its biological functions and phosphorylation is an important regulator of mGluR5 trafficking and function. We previously reported that striatal-enriched protein tyrosine phosphatase 61 (STEP₆₁) interacts with mGluR5 in a proteomics study of the STEP₆₁ interactome. Here, we explored the relationship between STEP₆₁ and mGluR5 in greater detail and find that STEP₆₁, like mGluR5, is preferentially localizes to extra-synaptic sites in neurons using electron microscopy. A systematic evaluation of STEP₆₁ in heterologous cells identifies its kinase-interacting and amino-terminal domains as being important for mGluR5 binding. Interestingly, we find that STEP₆₁ decreases mGluR5 surface and total protein levels in both heterologous cells and neurons in a lysosome-dependent manner. Conversely, mGluR5 protein and tyrosine phosphorylation levels are increased in STEP knockout (KO) mouse brain. There are four tyrosine residues in the cytosolic tail region of mGluR5, and their mutation decreases total and surface receptor protein levels. Together, these findings reveal an important role of STEP₆₁-mediated tyrosine dephosphorylation as a negative regulator of mGluR5 surface protein levels and stability.