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The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons

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Abstract

The metabotropic glutamate (mGlu) receptor 5 is a G protein-coupled receptor and is densely expressed in the mammalian brain. Like other glutamate receptors, mGlu5 receptors are tightly regulated by posttranslational modifications such as phosphorylation, although underlying mechanisms are incompletely investigated. In this study, we investigated the role of a prime kinase, extracellular signal-regulated kinase 1 (ERK1), in the phosphorylation and regulation of mGlu5 receptors in vitro and in striatal neurons. We found that recombinant ERK1 proteins directly bound to the C-terminal tail (CT) of mGlu5 receptors in vitro. Endogenous ERK1 also interacted with mGlu5 receptor proteins in adult rat striatal neurons in vivo. The kinase showed the ability to phosphorylate mGlu5 receptors. A serine residue in the distal region of mGlu5 CT was found to be a primary phosphorylation site sensitive to ERK1. In functional studies, we found that pharmacological inhibition of ERK with an inhibitor U0126 reduced the efficacy of mGlu5 receptors in stimulating production of cytoplasmic inositol-1,4,5-triphosphate, a major downstream conventional signaling event, in striatal neurons under normal conditions. These results identify mGlu5 as a new biochemical substrate of ERK1. The kinase can interact with and phosphorylate an intracellular domain of mGlu5 receptors in striatal neurons and thereby control its signaling efficacy.

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Funding

This work was supported by NIH grants DA10355 (J.Q.W.) and MH61469 (J.Q.W.).

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Authors and Affiliations

  1. Department of Biomedical Sciences, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO, 64108, USA

    Dao-Zhong Jin, Li-Min Mao & John Q. Wang

  2. Department of Anesthesiology, School of Medicine, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO, 64108, USA

    John Q. Wang

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  1. Dao-Zhong Jin
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  2. Li-Min Mao
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Correspondence to Dao-Zhong Jin or John Q. Wang.

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All animal use procedures were in strict accordance with the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Institutional Animal Care and Use Committee.

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The authors declare that they have no conflict of interest.

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Jin, DZ., Mao, LM. & Wang, J.Q. The Role of Extracellular Signal-Regulated Kinases (ERK) in the Regulation of mGlu5 Receptors in Neurons. J Mol Neurosci 66, 629–638 (2018). https://doi.org/10.1007/s12031-018-1193-0

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  • DOI: https://doi.org/10.1007/s12031-018-1193-0

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