title: Amphetamine increases phosphorylation of MAPK/ERK at synaptic sites in the rat striatum and medial prefrontal cortex.
abstract: Mitogen-activated protein kinases (MAPKs) play a central role in cell signaling. Extracellular signal-regulated kinase (ERK) is a prototypic subclass of MAPKs and is densely expressed in postmitotic neurons of adult mammalian brains. Active ERK translocates into the nucleus to regulate gene expression. Additionally, ERK is visualized in neuronal peripheries, such as distal synaptic structures. While nuclear ERK is a known sensitive target of psychostimulants, little is known about the responsiveness of synaptic ERK to stimulants. In this study, we focused on ERK at synaptic versus extrasynaptic sites and investigated its responses to the psychostimulant amphetamine in the adult rat striatum and medial prefrontal cortex (mPFC) in vivo. We used a pre-validated biochemical fractionation procedure to isolate synapse- and extrasynapse-enriched membranes. We found that two common ERK isoforms (ERK1 and ERK2) were concentrated more in extrasynaptic fractions than in synaptic fractions in striatal and cortical neurons under normal conditions. At synaptic sites, ERK2 was noticeably more abundant than ERK1. Acute injection of amphetamine induced an increase in ERK2 phosphorylation in the synaptic fraction of striatal neurons, while the drug did not alter extrasynaptic ERK2 phosphorylation. Similar results were observed in the mPFC. In both synaptic and extrasynaptic compartments, total ERK1/2 proteins remained stable in response to amphetamine. Our data establish the subsynaptic distribution pattern of MAPK/ERK in striatal and cortical neurons. Moreover, the synaptic pool of ERK2 in these neurons can be selectively activated by amphetamine.
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Mao
authors.forename: James M
authors.initials: JM
authors.lastname: Reusch
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Fibuch
authors.forename: Zhenguo
authors.initials: Z
authors.lastname: Liu
authors.forename: John Q
authors.initials: JQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology*; D003913:Dextroamphetamine / Q000494:pharmacology*; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013570:Synaptic Membranes / Q000187:drug effects / Q000201:enzymology*
chemical_list: D000697:Central Nervous System Stimulants; D007527:Isoenzymes; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003913:Dextroamphetamine