| First Author | Marks CR | Year | 2018 |
| Journal | Mol Pharmacol | Volume | 94 |
| Issue | 6 | Pages | 1352-1362 |
| PubMed ID | 30282777 | Mgi Jnum | J:286220 |
| Mgi Id | MGI:6402337 | Doi | 10.1124/mol.118.113142 |
| Citation | Marks CR, et al. (2018) Activated CaMKIIalpha Binds to the mGlu5 Metabotropic Glutamate Receptor and Modulates Calcium Mobilization. Mol Pharmacol 94(6):1352-1362 |
| abstractText | Ca(2+)/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 CaMKIIalpha 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) CaMKIIalpha However, the binding of CaMKIIalpha to this CTD fragment is reduced by the addition of excess Ca(2+)/calmodulin or by additional CaMKIIalpha autophosphorylation at non-Thr286 sites. Furthermore, in vitro binding of CaMKIIalpha 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 CaMKIIalpha 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 CaMKIIalpha with mGlu5a in heterologous cells. First, cell-surface biotinylation studies showed that CaMKIIalpha increases the surface expression of mGlu5a Second, using Ca(2+) fluorimetry and single-cell Ca(2+) imaging, we found that CaMKIIalpha reduces the initial peak of mGlu5a-mediated Ca(2+) mobilization by about 25% while doubling the relative duration of the Ca(2+) signal. These findings provide new insights into the physical and functional coupling of these key regulators of postsynaptic signaling. |
