Metabotropic glutamate receptor internalization and synaptic AMPA receptor endocytosis by dopamine

Group I metabotropic glutamate receptors (mGluRs) play important roles in synaptic function and plasticity, and in many neuropsychiatric disorders. Trafficking plays crucial roles in proper targeting of these receptors in specific regions of the neuron and in regulating the activity of these receptors. Group I mGluRs encounter dopamine in various regions of the brain and multiple findings suggest that dopamine regulates these receptors in the hippocampus. We show here that dopamine induces internalization of both members of the group I mGluR family, mGluR1 (also known as GRM1) and mGluR5 (GRM5), in hippocampal neurons derived from mice through a clathrin-dependent but dynamin-independent pathway. Dopamine increases mGluR-mediated Gαq (also known as GNAQ) activity and phosphorylation of MAP kinases. Following dopamine-mediated internalization, receptors recycle to the cell surface faster than the recycling of agonist-mediated internalized receptors. Recycling of the dopamine-mediated internalized mGluR1 is protein phosphatase 2B dependent. Finally, we report that dopamine also induces mGluR-mediated synaptic AMPA receptor endocytosis, the cellular correlate of mGluR-dependent synaptic plasticity. Thus, this study unravels a novel role for dopamine in the internalization of mGluRs and mGluR-mediated AMPA receptor endocytosis.