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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH061469-13
Application #
8417726
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
2000-04-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
13
Fiscal Year
2013
Total Cost
$356,400
Indirect Cost
$118,800
Name
University of Missouri Kansas City
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
He, Nan; Mao, Li-Min; Sturich, Adrian W et al. (2018) Inhibition of basal and amphetamine-stimulated extracellular signal-regulated kinase (ERK) phosphorylation in the rat forebrain by muscarinic acetylcholine M4 receptors. Brain Res 1688:103-112
Xue, Bing; Mao, Li-Min; Jin, Dao-Zhong et al. (2018) Pharmacological modulation of AMPA receptor phosphorylation by dopamine and muscarinic receptor agents in the rat medial prefrontal cortex. Eur J Pharmacol 820:45-52
Jin, Dao-Zhong; Mao, Li-Min; Wang, John Q (2018) The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons. J Mol Neurosci 66:629-638
Mao, Li-Min; Faris, Hunter J; Wang, John Q (2018) Muscarinic Acetylcholine Receptors Inhibit Fyn Activity in the Rat Striatum In Vivo. J Mol Neurosci 64:523-532
Mao, Li-Min; He, Nan; Jin, Dao-Zhong et al. (2018) Regulation of Phosphorylation of AMPA Glutamate Receptors by Muscarinic M4 Receptors in the Striatum In vivo. Neuroscience 375:84-93
Mao, Li-Min; Wang, John Q (2018) Alterations in mGlu5 receptor expression and function in the striatum in a rat depression model. J Neurochem 145:287-298
Mao, Li-Min; Wang, John Q (2017) Antagonism of Dopamine D2 Receptors Alters Phosphorylation of Fyn in the Rat Medial Prefrontal Cortex. J Mol Neurosci 61:524-530
Mao, Li-Min; Wang, Henry H; Wang, John Q (2017) Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain. Neurochem Res 42:1202-1210
Yang, Ju Hwan; Mao, Li-Min; Choe, Eun Sang et al. (2017) Synaptic ERK2 Phosphorylates and Regulates Metabotropic Glutamate Receptor 1 In Vitro and in Neurons. Mol Neurobiol 54:7156-7170
Jin, Dao-Zhong; Mao, Li-Min; Wang, John Q (2017) An Essential Role of Fyn in the Modulation of Metabotropic Glutamate Receptor 1 in Neurons. eNeuro 4:

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