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Activated CaMKII Binds to the mGlu Metabotropic Glutamate Receptor and Modulates Calcium Mobilization.

Marks CR, Shonesy BC, Wang X, Stephenson JR, Niswender CM, Colbran RJ
Mol Pharmacol. 2018 94 (6): 1352-1362

PMID: 30282777 · PMCID: PMC6207916 · DOI:10.1124/mol.118.113142

Ca/calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu is present in CaMKII complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu directly interacts with purified Thr286-autophosphorylated (activated) CaMKII However, the binding of CaMKII to this CTD fragment is reduced by the addition of excess Ca/calmodulin or by additional CaMKII autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKII is dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866-868 of the mGlu-CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKII with full-length mGlu expressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKII with mGlu in heterologous cells. First, cell-surface biotinylation studies showed that CaMKII increases the surface expression of mGlu Second, using Ca fluorimetry and single-cell Ca imaging, we found that CaMKII reduces the initial peak of mGlu-mediated Ca mobilization by about 25% while doubling the relative duration of the Ca signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling.

Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

MeSH Terms (16)

Animals Calcium Calcium-Calmodulin-Dependent Protein Kinase Type 2 Calmodulin Cell Line Cell Membrane Female HEK293 Cells Humans Immunoprecipitation Male Mice Mice, Knockout Protein Binding Receptor, Metabotropic Glutamate 5 Signal Transduction

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