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Differential regulation of CaMK IIα interactions with m G luR5 and NMDA receptors by C a 2+ in neurons
Author(s) -
Jin DaoZhong,
Guo MingLei,
Xue Bing,
Mao LiMin,
Wang John Q.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12434
Subject(s) - metabotropic glutamate receptor 5 , microbiology and biotechnology , ionotropic effect , metabotropic glutamate receptor , nmda receptor , metabotropic glutamate receptor 1 , chemistry , glutamate receptor , neurotransmission , metabotropic receptor , receptor , biology , biochemistry
Two glutamate receptors, metabotropic glutamate receptor 5 ( mG luR5), 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 mG luR5 in vitro . This binding is state‐dependent: inactive CaMKIIα binds to mG luR5 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 mG luR5 at a region overlapping with the CaMKIIα‐binding site, resulting in a competitive inhibition of CaMKIIα binding to mG luR5. In rat striatal neurons, inactive CaMKIIα constitutively binds to mG luR5. Activation of mG luR5 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 mG luR5 seems to serve as a scaffolding domain to recruit and store CaMKIIα within synapses. The mG luR5‐dependent Ca 2+ transients differentially regulate CaMKIIα interactions with mG luR5 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.