title: Differential regulation of CaMKIIα interactions with mGluR5 and NMDA receptors by Ca(2+) in neurons.
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 Ca(2+) /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 Ca(2+) -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 Ca(2+) 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 Ca(2+) release in striatal neurons. Released Ca(2+) 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.
authors.affiliation: Department of Basic Medical Science, School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.
authors.forename: Dao-Zhong
authors.initials: DZ
authors.lastname: Jin
authors.forename: Ming-Lei
authors.initials: ML
authors.lastname: Guo
authors.forename: Bing
authors.initials: B
authors.lastname: Xue
authors.forename: Li-Min
authors.initials: LM
authors.lastname: Mao
authors.forename: John Q
authors.initials: JQ
authors.lastname: Wang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002147:Calmodulin / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D002135:Calcium-Binding Proteins; D002147:Calmodulin; C581829:Camk2n1 protein, rat; D002352:Carrier Proteins; C578937:Grm5 protein, rat; C121001:NR2B NMDA receptor; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D002118:Calcium
keywords: GluN2B; NR2B; calmodulin; mGluR; nucleus accumbens; striatum
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