Protein phosphorylation is an important mechanism for post-translational regulation of glutamate receptors. Through phosphorylating a specific amino acid in the intracellular domain, protein kinases regulate anchoring, trafficking, and signaling of a given glutamate receptor. Group I metabotropic glutamate receptors (mGluR1/5) are densely expressed in the striatum, a brain area involved in addictive properties of psychostimlants. The long-form mGluR1/5 splice variants (1a, 5a, and 5b) have a large intracellular C-terminal tail, which provides a basis for direct protein-protein interactions and phosphorylation. In our recent studies, we found that Ca2+/calmodulin-dependent protein kinase II (CaMKII) binds directly to the proximal region of mGluR5a C-terminus. This binding converts mGluR5a into a biochemical substrate for phosphorylation likely at a selective serine site. These findings raise innovative questions as to if CaMKII regulates mGluR1/5 via a direct protein-protein interaction and phosphorylation and if this regulation has a high clinical relevance in a disease model. In this continuation proposal, a series of coherent experiments from molecule to behavior was proposed to confirm the direct binding of CaMKII to mGluR1/5 in vitro and to establish that native CaMKII and mGluR1/5 interact with each other in striatal neurons in vivo. We will characterize if and how Ca2+ regulates the interaction between CaMKII and mGluR1/5 in vitro and in vivo. We will then investigate whether Ca2+-regulated CaMKII-mGluR1/5 interactions regulate 1) signaling efficacy of mGluR1/5, 2) trafficking of the receptors, and 3) interactions of mGluR1/5 with key scaffold Homer proteins, in striatal neurons or heterologous cells. Finally, we will carry out neurobehavioral experiments to define the role of CaMKII-mGluR1/5 interactions in the addictive action of the psychostimulant amphetamine. Our results will provide evidence and insights for a new synaptic model of kinase-regulated mGluRs and for its linkage to a mental illness (substance addiction). They will also ultimately contribute to the development of novel pharmacotherapies, by targeting mGluRs and CaMKII, for treating various mental illnesses, including addiction.

Public Health Relevance

This research project is aimed to elucidate molecular mechanisms underlying the regulation of metabotropic glutamate receptors and roles of the receptor in drugs of abuse. The information obtained through this project is valuable for the development of new pharmacotherapies for mental illnesses stemming from dysfunctional glutamatergic transmission in the central nervous system.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Nadler, Laurie S
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University of Missouri Kansas City
Other Basic Sciences
Schools of Medicine
Kansas City
United States
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Mao, Li-Min; Wang, John Q (2016) Tyrosine phosphorylation of glutamate receptors by non-receptor tyrosine kinases: roles in depression-like behavior. Neurotransmitter (Houst) 3:
Xue, Bing; Fitzgerald, Cole A; Jin, Dao-Zhong et al. (2016) Amphetamine elevates phosphorylation of eukaryotic initiation factor 2α (eIF2α) in the rat forebrain via activating dopamine D1 and D2 receptors. Brain Res 1646:459-66
Mao, Li-Min; Wang, John Q (2016) Dopamine D2 receptors are involved in the regulation of Fyn and metabotropic glutamate receptor 5 phosphorylation in the rat striatum in vivo. J Neurosci Res 94:329-38
Mao, Li-Min; Wang, John Q (2016) Regulation of Group I Metabotropic Glutamate Receptors by MAPK/ERK in Neurons. J Nat Sci 2:
Yang, Ju Hwan; Mao, Li-Min; Choe, Eun Sang et al. (2016) Synaptic ERK2 Phosphorylates and Regulates Metabotropic Glutamate Receptor 1 In Vitro and in Neurons. Mol Neurobiol :
Mao, Li-Min; Wang, John Q (2016) Synaptically Localized Mitogen-Activated Protein Kinases: Local Substrates and Regulation. Mol Neurobiol 53:6309-6315
Mao, Li-Min; Xue, Bing; Jin, Dao-Zhong et al. (2015) Dynamic increases in AMPA receptor phosphorylation in the rat hippocampus in response to amphetamine. J Neurochem 133:795-805
Xue, Bing; Mao, Li-Min; Jin, Dao-Zhong et al. (2015) Regulation of synaptic MAPK/ERK phosphorylation in the rat striatum and medial prefrontal cortex by dopamine and muscarinic acetylcholine receptors. J Neurosci Res 93:1592-9
Mao, Li-Min; Wang, John Q (2015) Dopaminergic and cholinergic regulation of Fyn tyrosine kinase phosphorylation in the rat striatum in vivo. Neuropharmacology 99:491-9
Jin, Dao-Zhong; Xue, Bing; Mao, Li-Min et al. (2015) Metabotropic glutamate receptor 5 upregulates surface NMDA receptor expression in striatal neurons via CaMKII. Brain Res 1624:414-23

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