title: Phosphorylation and feedback regulation of metabotropic glutamate receptor 1 by calcium/calmodulin-dependent protein kinase II.
abstract: The metabotropic glutamate receptor 1 (mGluR1) is a Gα(q)-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, Ca²⁺/calmodulin-dependent protein kinase IIα (CaMKIIα), directly binds to the intracellular C terminus (CT) of mGluR1a. This binding is augmented by Ca²⁺ 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 Ca²⁺-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 Ca²⁺-dependent protein-protein interaction between a synaptic kinase and mGluR1, which constitutes a feedback loop facilitating desensitization of mGluR1a.
authors: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
authors: Dao-Zhong
authors: DZ
authors: Jin
authors: Ming-Lei
authors: ML
authors: Guo
authors: Bing
authors: B
authors: Xue
authors: Eugene E
authors: EE
authors: Fibuch
authors: Eun Sang
authors: ES
authors: Choe
authors: Li-Min
authors: LM
authors: Mao
authors: John Q
authors: JQ
authors: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism / Q000502:physiology*; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D025461:Feedback, Physiological / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2