Fig. 1.

Ca²⁺-activated CaM differentially regulates trafficking of mGlu5 versus mGlu7 receptors. In the postsynaptic compartments, Ca²⁺-CaM binds to mGlu5 at a single critical residue, L896, and stabilizes mGlu5 on the postsynaptic plasma membrane. Treatment with the agonist DHPG or PKC activation dissociates CaM binding, increases S901 phosphorylation of mGlu5, and induces mGlu5 endocytosis (Choi et al., 2011; Ko et al., 2012; Lee et al., 2008b). Siah-1A competes with CaM for mGlu5 binding, increases agonist-induced endosomal trafficking, and degrades mGlu5 in lysosomes (Ishikawa et al., 1999; Ko et al., 2012). CaMKIIα dissociates from mGlu5 in competition with CaM and increases agonist-induced receptor endocytosis upon mGlu5-stimulated Ca²⁺ release (Jin et al., 2013b; Raka et al., 2015). In the presynaptic compartment, CaM reduces PKC-induced phosphorylation of mGlu7 S862 and facilitates endocytosis of mGlu7. PICK1 augments the PKC-induced S862 phosphorylation of mGlu7, enhances stable surface expression of mGlu7, and competes with CaM for binding to mGlu7. PP1γ1 inhibits constitutive and agonist L-AP4-induced internalization of mGlu7 (Suh et al., 2013; Suh et al., 2008). At resting state, RIM1α and munc13-1 are sequestered by mGlu7. After prolonged mGlu7 activation, munc13-1, which may compete with CaM, is translocated from mGlu7 to associate with RIM1α and enhance synaptic vesicle exocytosis (Ferrero et al., 2016; Martin et al., 2010; Mochida, 2011; Pelkey et al., 2008). CaM also competes with G_βγ, CaBP1, MacMARCKS, MAP1B, and Norbin (Bertaso et al., 2006; Moritz et al., 2009; Nakajima, 2011; O’Connor et al., 1999; Wang et al., 2009).