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 #
5R01MH061469-14
Application #
8618920
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
2014-03-01
Budget End
2015-02-28
Support Year
14
Fiscal Year
2014
Total Cost
$371,250
Indirect Cost
$123,750
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
Mao, Li-Min; Jin, Dao-Zhong; Xue, Bing et al. (2014) Phosphorylation and regulation of glutamate receptors by CaMKII. Sheng Li Xue Bao 66:365-72
Wang, John Q; Guo, Ming-Lei; Jin, Dao-Zhong et al. (2014) Roles of subunit phosphorylation in regulating glutamate receptor function. Eur J Pharmacol 728:183-7
Xue, Bing; Edwards, Matthew C; Mao, Li-Min et al. (2014) Rapid and sustained GluA1 S845 phosphorylation in synaptic and extrasynaptic locations in the rat forebrain following amphetamine administration. Neurochem Int 64:48-54
Song, Lu; Yang, Xinxin; Ma, Yaping et al. (2014) The CB1 cannabinoid receptor agonist reduces L-DOPA-induced motor fluctuation and ERK1/2 phosphorylation in 6-OHDA-lesioned rats. Drug Des Devel Ther 8:2173-9
Mao, Li-Min; Hastings, James M; Fibuch, Eugene E et al. (2014) Propofol selectively alters GluA1 AMPA receptor phosphorylation in the hippocampus but not prefrontal cortex in young and aged mice. Eur J Pharmacol 738:237-44
Mao, Li-Min; Diaz, Jesus A; Fibuch, Eugene E et al. (2013) Regulation of phosphorylation of synaptic and extrasynaptic GluA1 AMPA receptors in the rat forebrain by amphetamine. Eur J Pharmacol 715:164-71
Mao, Li-Min; Reusch, James M; Fibuch, Eugene E et al. (2013) Amphetamine increases phosphorylation of MAPK/ERK at synaptic sites in the rat striatum and medial prefrontal cortex. Brain Res 1494:101-8
Guo, Ming-Lei; Xue, Bing; Jin, Dao-Zhong et al. (2013) Dynamic downregulation of Nogo receptor expression in the rat forebrain by amphetamine. Neurochem Int 63:195-200
Jin, Dao-Zhong; Guo, Ming-Lei; Xue, Bing et al. (2013) Differential regulation of CaMKII? interactions with mGluR5 and NMDA receptors by Ca(2+) in neurons. J Neurochem 127:620-31
Jin, Dao-Zhong; Guo, Ming-Lei; Xue, Bing et al. (2013) Phosphorylation and feedback regulation of metabotropic glutamate receptor 1 by calcium/calmodulin-dependent protein kinase II. J Neurosci 33:3402-12

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