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; 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
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; 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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