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; 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
Carino, Charlene; Fibuch, Eugene E; Mao, Li-Min et al. (2012) Dynamic loss of surface-expressed AMPA receptors in mouse cortical and striatal neurons during anesthesia. J Neurosci Res 90:315-23

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