Regulation of MAPK/ERK phosphorylation via ionotropic glutamate receptors in cultured rat striatal neurons

Authors

  • Limin Mao,

    1. Department of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes Street, Rm. M3-225, Kansas City, Missouri 64108, USA
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  • Qingsong Tang,

    1. Department of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes Street, Rm. M3-225, Kansas City, Missouri 64108, USA
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  • Shazia Samdani,

    1. Department of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes Street, Rm. M3-225, Kansas City, Missouri 64108, USA
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  • Zhenguo Liu,

    1. Department of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes Street, Rm. M3-225, Kansas City, Missouri 64108, USA
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  • John Q. Wang

    1. Department of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes Street, Rm. M3-225, Kansas City, Missouri 64108, USA
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: Dr J. Q. Wang, as above.
E-mail: wangjq@umkc.edu

Abstract

Extracellular signals may regulate mitogen-activated protein kinase (MAPK) cascades through a receptor-mediated mechanism. As a signaling superhighway to the nucleus, active Ras-MAPK cascades phosphorylate transcription factors and facilitate gene expression. In cultured rat striatal neurons, the present work systemically examined the linkage between glutamate receptors and the extracellular signal-regulated kinase 1/2 (ERK1/2) subclass of MAPK. We found that glutamate induced a rapid and transient phosphorylation of ERK1/2. Similar responses of ERK1/2 phosphorylation were also induced by the ligands selective for each of three subtypes of ionotropic receptors (NMDA, AMPA and kainate), although not by the subgroup-selective agonists for three subgroups of metabotropic glutamate receptors after 8–9 days in culture. The ERK1/2 phosphorylation induced by all ionotropic receptor agents was dose-, time- and Ca2+ influx-dependent and occurred in neurons, but not glia. The NMDA-, AMPA- and kainate-induced ERK1/2 phosphorylation was blocked only by the antagonists selective for respective subtypes. The ERK1/2 phosphorylation induced by these agents was also sensitive to the MAPK kinase 1 (MEK1) inhibitor PD98059 and the MEK1/2 inhibitor U0126. In a further attempt to evaluate the role of active ERK1/2 in activating a downstream transcription factor cAMP response element-binding protein (CREB), NMDA, AMPA, and kainate were found to increase CREB phosphorylation. The NMDA- and AMPA/kainate-induced CREB phosphorylation was completely and partially blocked by U0126, respectively. These results revealed a positive linkage between ionotropic glutamate receptors and MEK-sensitive ERK1/2 phosphorylation in striatal neurons. The active ERK1/2 cascade activates the downstream transcription factor CREB to participate in the regulation of gene expression.

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