Differential regulation of CaMKIIα interactions with mGluR5 and NMDA receptors by Ca2+ in neurons

Authors

  • Dao-Zhong Jin,

    1. Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
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  • Ming-Lei Guo,

    1. Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
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  • Bing Xue,

    1. Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
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  • Li-Min Mao,

    1. Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
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  • John Q. Wang

    Corresponding author
    1. Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
    2. Department of Anesthesiology, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA
    • Address correspondence and reprint requests to Dr. John Q. Wang, Department of Basic Medical Science, University of Missouri-Kansas City, School of Medicine, 2411 Holmes Street, Kansas City, MO 64108, USA. E-mail: wangjq@umkc.edu

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Abstract

Two glutamate receptors, metabotropic glutamate receptor 5 (mGluR5), and ionotropic NMDA receptors (NMDAR), functionally interact with each other to regulate excitatory synaptic transmission in the mammalian brain. In exploring molecular mechanisms underlying their interactions, we found that Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) may play a central role. The synapse-enriched CaMKIIα directly binds to the proximal region of intracellular C terminal tails of mGluR5 in vitro. This binding is state-dependent: inactive CaMKIIα binds to mGluR5 at a high level whereas the active form of the kinase (following Ca2+/calmodulin binding and activation) loses its affinity for the receptor. Ca2+ also promotes calmodulin to bind to mGluR5 at a region overlapping with the CaMKIIα-binding site, resulting in a competitive inhibition of CaMKIIα binding to mGluR5. In rat striatal neurons, inactive CaMKIIα constitutively binds to mGluR5. Activation of mGluR5 Ca2+-dependently dissociates CaMKIIα from the receptor and simultaneously promotes CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα-sensitive site. Together, the long intracellular C-terminal tail of mGluR5 seems to serve as a scaffolding domain to recruit and store CaMKIIα within synapses. The mGluR5-dependent Ca2+ transients differentially regulate CaMKIIα interactions with mGluR5 and GluN2B in striatal neurons, which may contribute to cross-talk between the two receptors.

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We show that activation of mGluR5 with a selective agonist triggers intracellular Ca2+ release in striatal neurons. Released Ca2+ dissociates preformed CaMKIIα from mGluR5 and meanwhile promotes active CaMKIIα to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKIIα to phosphorylate GluN2B at a CaMKIIα-sensitive site. This agonist-induced cascade seems to mediate crosstalk between mGluR5 and NMDA receptors in neurons.

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