The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) is enriched in synaptic structures. Recently, we found that synaptic ERK directly binds to group I metabotropic glutamate receptors (mGluR1 and mGluR5) and phosphorylates mGluR5a at a cluster of serine sites in the C-terminal region. These findings for the first time provide direct evidence supporting a synaptic G protein-coupled receptor as a nonnuclear substrate of ERK. Encouraged by this new discovery, we propose this renewal application to further profile this previously unrecognized ERK-mGluR1/5 coupling at synaptic sites and define its roles in glutamate receptor plasticity and psychostimulant addiction. Our overarching and expanded hypothesis is that MAPK/ERK regulates synaptic mGluR1/5 physiology and links mGluR1/5 plasticity to stimulant addiction. Using multidisciplinary approaches, this hypothesis will be tested both in vitro and in vivo, as appropriate, in the four inter-supportive Aims.
Specific Aim I will identify accurate ERK-mediated phosphorylation sites in mGluR1 and mGluR5 and will characterize the biochemical and enzymatic properties of mGluR1/5 phosphorylation.
Specific Aim II will confirm the interaction of native ERK with mGluR1/5 at synaptic sites in neurons and will determine whether the ERK-mediated phosphorylation is a regulatory event and is subject to the activity-dependent modulation by changing synaptic inputs.
Specific Aim III will evaluate the physiological relevance of ERK-mGluR1/5 interactions. The role of ERK in regulating mGluR1/5 expression and function and underlying mechanisms will be investigated in neurons or heterologous cells. Finally, Specific IV will define the pathophysiological relevance of the synaptic ERK-mGluR1/5 coupling in psychostimulant addiction. Both conditioned place preference and self-administration paradigms are utilized to assess its role in amphetamine seeking behavior. Results achieved here will conceptually advance the understanding of network glutamate receptor signaling and will contribute to the development of novel pharmacotherapies, by targeting MAPK/ERK and mGluR1/5, for the treatment of stimulant addiction or various mental illnesses stemmed from drug abuse.

Public Health Relevance

This research project investigates phosphorylation and regulation of metabotropic glutamate receptors and roles of the receptor in drugs of abuse. The information obtained through this project is valuable for the understanding of glutamate receptor biology and development of new pharmacotherapies for treatment of addictive disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
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Wu, Da-Yu
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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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