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

Dao Zhong Jin, Minglei Guo, Bing Xue, Li Min Mao, John Q. Wang

Research output: Contribution to journalArticle

23 Citations (Scopus)

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 Ca 2+/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. Ca 2+ 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. 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. We show that activation of mGluR5 with a selective agonist triggers intracellular Ca 2+ 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.

Original languageEnglish (US)
Pages (from-to)620-631
Number of pages12
JournalJournal of Neurochemistry
Volume127
Issue number5
DOIs
StatePublished - Dec 1 2013

Fingerprint

Metabotropic Glutamate 5 Receptor
Calcium-Calmodulin-Dependent Protein Kinase Type 2
N-Methyl-D-Aspartate Receptors
Neurons
Corpus Striatum
Chemical activation
Calmodulin
Crosstalk
Synapses
Tail

Keywords

  • GluN2B
  • NR2B
  • calmodulin
  • mGluR
  • nucleus accumbens
  • striatum

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Differential regulation of CaMKIIα interactions with mGluR5 and NMDA receptors by Ca2+ in neurons. / Jin, Dao Zhong; Guo, Minglei; Xue, Bing; Mao, Li Min; Wang, John Q.

In: Journal of Neurochemistry, Vol. 127, No. 5, 01.12.2013, p. 620-631.

Research output: Contribution to journalArticle

Jin, Dao Zhong ; Guo, Minglei ; Xue, Bing ; Mao, Li Min ; Wang, John Q. / Differential regulation of CaMKIIα interactions with mGluR5 and NMDA receptors by Ca2+ in neurons. In: Journal of Neurochemistry. 2013 ; Vol. 127, No. 5. pp. 620-631.
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