Activated CaMKII α Binds to the mGlu 5 Metabotropic Glutamate Receptor and Modulates Calcium Mobilization.

Ca2+ /calmodulin-dependent protein kinase II (CaMKII) and metabotropic glutamate receptor 5 (mGlu5 ) are critical signaling molecules in synaptic plasticity and learning/memory. Here, we demonstrate that mGlu5 is present in CaMKII α complexes isolated from mouse forebrain. Further in vitro characterization showed that the membrane-proximal region of the C-terminal domain (CTD) of mGlu5a directly interacts with purified Thr286-autophosphorylated (activated) CaMKII α However, the binding of CaMKII α to this CTD fragment is reduced by the addition of excess Ca2+ /calmodulin or by additional CaMKII α autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKII α is dependent on a tribasic residue motif Lys-Arg-Arg (KRR) at residues 866-868 of the mGlu5a -CTD, and mutation of this motif decreases the coimmunoprecipitation of CaMKII α with full-length mGlu5a expressed in heterologous cells by about 50%. The KRR motif is required for two novel functional effects of coexpressing constitutively active CaMKII α with mGlu5a in heterologous cells. First, cell-surface biotinylation studies showed that CaMKII α increases the surface expression of mGlu5a Second, using Ca2+ fluorimetry and single-cell Ca2+ imaging, we found that CaMKII α reduces the initial peak of mGlu5a -mediated Ca2+ mobilization by about 25% while doubling the relative duration of the Ca2+ signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling.