The metabotropic glutamate receptor 1 (mGluR1) is a Gαq-protein-coupled receptor and is distributed in broad regions of the mammalian brain. As a key element in excitatory synaptic transmission, the receptor regulates a wide range of cellular and synaptic activities. In addition to regulating its targets, the receptor itself is believed to be actively regulated by intracellular signals, although underlying mechanisms are essentially unknown. Here we found that a synapse-enriched protein kinase, Ca 2+ /calmodulin-dependent protein kinase IIα (CaMKIIα), directly binds to the intracellular C terminus (CT) of mGluR1a. This binding is augmented by Ca 2+ in vitro. The direct interaction promotes CaMKIIα to phosphorylate mGluR1a at a specific threonine site (T871). In rat striatal neurons, the mGluR1 agonist triggers the receptor-associated phosphoinositide signaling pathway to induce Ca 2+ -dependent recruitment of CaMKIIα to mGluR1a-CT. This enables the kinase to inhibit the response of the receptor to subsequent agonist exposure. Our data identify an agonist-induced and Ca 2+ -dependent protein-protein interaction between a synaptic kinase and mGluR1, which constitutes a feedback loop facilitating desensitization of mGluR1a.
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