A vital role for PICK1 in the differential regulation of metabotropic glutamate receptor internalization and synaptic AMPA receptor endocytosis

Group I metabotropic glutamate receptors (mGluRs) play important roles in many neuronal processes and are believed to be involved in synaptic plasticity underlying the encoding of experience, including classic paradigms of learning and memory. These receptors have also been implicated in various neurodevelopmental disorders, such as Fragile X syndrome and autism. Internalization and recycling of these receptors in the neuron are important mechanisms to regulate the activity of the receptor and control the precise spatiotemporal localization of these receptors. Applying a “molecular replacement” approach in hippocampal neurons derived from mice, we demonstrate a critical role for protein interacting with C kinase 1 (PICK1) in regulating the agonist-induced internalization of mGluR1. We show that PICK1 specifically regulates the internalization of mGluR1, but it does not play any role in the internalization of the other member of group I mGluR family, mGluR5. Various regions of PICK1 viz., the N-terminal acidic motif, PDZ domain, and BAR domain play important roles in the agonist-mediated internalization of mGluR1. Finally, we demonstrate that PICK1-mediated internalization of mGluR1 is critical for the resensitization of the receptor. Upon knockdown of endogenous PICK1, mGluR1s stayed on the cell membrane as inactive receptors, incapable of triggering the MAP kinase signaling. They also could not induce AMPAR endocytosis, a cellular correlate for mGluR-dependent synaptic plasticity. Thus, this study unravels a novel role for PICK1 in the agonist-mediated internalization of mGluR1 and mGluR1-mediated AMPAR endocytosis that might contribute to the function of mGluR1 in neuropsychiatric disorders.