The Role of CaMKII in mGlu5 Signaling

Ca 2+ /calmodulin (CaM)‐dependent protein kinase II (CaMKII) is a serine/threonine kinase that accounts for ~1% of total protein in forebrain. Interactions of activated CaMKII with CaMKII associated proteins (CaMKAPs) and roles of CaMKII in modulating ionotropic glutamate receptors and voltage gated ion channels have been studied intensively, but the role of CaMKII in G protein coupled receptor (GPCR) regulation is less well understood. Here, we confirmed a previous report1 that CaMKII interacts with the metabotropic glutamate receptor 5 (mGlu5), a G q coupled receptor, in vitro , in HEK293 cells and in mouse forebrain lysates. Unlike most other CaMKAPs, mGlu5a interacts with INACTIVE CaMKII, and the interaction is disrupted by Ca 2+ /CaM. We also found that CaMKII phosphorylates the mGlu5a C‐terminal domain (CTD) in vitro . Inclusion of the mGlu5b‐specific splice insert in the CTD does not affect the binding or phosphorylation of mGlu5 by CaMKII. We have begun to characterize CaMKII binding and phosphorylation sites in mGlu5a/b. Binding of Ca 2+ /CaM to mGlu5 blocks the phosphorylation of some sites on mGlu5, such that they are preferentially phosphorylated by Thr 286 ‐autophosphorylated CaMKII, which exhibits Ca 2+ /CaM‐independent kinase activity. In addition, initial studies indicate that the mGlu5 CTD modulates CaMKII activation in vitro , representing a potential bidirectional regulatory mechanism. We are currently comparing CaMKII activity and subcellular localization in wild‐type and mGlu5‐null mice. Understanding the interplay between these key synaptic regulators may provide mechanistic insights into their role in the modulation of synaptic transmission. Support or Funding Information T32‐DK007563 and AHA 15PRE25110020 to CRM R01‐MH063232 and R01‐NS078291 to RJC