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

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 II (CaMKII) may play a central role. The synapse-enriched CaMKII directly binds to the proximal region of intracellular C terminal tails of mGluR5 in vitro. This binding is state-dependent: inactive CaMKII 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 CaMKII-binding site, resulting in a competitive inhibition of CaMKII binding to mGluR5. In rat striatal neurons, inactive CaMKII constitutively binds to mGluR5. Activation of mGluR5 Ca2+-dependently dissociates CaMKII from the receptor and simultaneously promotes CaMKII to bind to the adjacent NMDAR GluN2B subunit, which enables CaMKII to phosphorylate GluN2B at a CaMKII-sensitive site. Together, the long intracellular C-terminal tail of mGluR5 seems to serve as a scaffolding domain to recruit and store CaMKII within synapses. The mGluR5-dependent Ca2+ transients differentially regulate CaMKII interactions with mGluR5 and GluN2B in striatal neurons, which may contribute to cross-talk between the two receptors.