Aβo alters mGluR5 trafficking in neurons, with reduced diffusion, clustering, aberrant activation, and neurotoxicity (Renner et al., 2010). The results here provide a PrPC-based mechanism for these findings and for downstream signaling. Direct coupling of PrPC to mGluR5 has been reported for an unrelated ligand, the
laminin gamma-1 selleck screening library chain (Beraldo et al., 2011). Aβo from synthetic, cellular, and human AD brain sources suppresses LTP and enhances LTD. These actions are mimicked by mGluR5 agonists and inhibited by mGluR5 antagonists (Rammes et al., 2011, Shankar et al., 2008 and Wang et al., 2004). In human AD, mGluR ligand binding is decreased in brain relative to controls and the loss is correlated with disease progression (Albasanz et al., 2005). Proteins titrated by mGluRs, eEF-2, Arc, and p70 S6 kinase are dysregulated in AD brain (An et al., 2003, Li et al., 2005 and Wu et al., 2011). Canonical mGluR5 signaling couples to Gq/G11 GTPases that activate phospholipase C to produce IP3 and release calcium stores (Lüscher and Huber, 2010). mGluR5 also modulates
plasma membrane potassium, calcium, and transient receptor potential channels. Src family tyrosine kinases, including Fyn, have been implicated in linking to NMDA-R (Heidinger et al., 2002 and Nicodemo Lumacaftor mw et al., 2010). The proline rich tyrosine kinase 2 (Pyk2) participates in Src/Fyn interaction with mGluR signaling (Heidinger et al., 2002 and Nicodemo et al., 2010). The calcium/calmodulin-dependent Ketanserin eEF2 kinase (eEF2K) is bound to mGluR5 in the basal state, but is released during activation to phosphorylate eEF2 (Lüscher and Huber, 2010).
Phospho-eEF2 reduces global translation, but allows increased Arc/Arg3.1 expression (Park et al., 2008). The Homer family plays a role in mGluR signaling, interacting with receptor and eEF2K (Hu et al., 2010, Lüscher and Huber, 2010 and Ronesi et al., 2012). Homer interactions with SHANK contribute to PSD localization, specific isoforms have roles in homeostatic scaling. We show that Aβo-PrPC complexes lead to several mGluR5 outputs. Fyn activation by Aβo in cortical neurons requires mGluR5 genetically and pharmacologically. Fyn is implicated in Aβo-induced dysregulation of NMDA-R trafficking and activation (Um et al., 2012). Because Fyn binds directly to Tau (Ittner et al., 2010 and Lee et al., 2004), this may have implications for AD beyond dysregulation of GluRs. The Aβo-PrPC-mGluR5 complex also activates phospholipase C, as detected by monitoring calcium-activated chloride channels in oocytes. The ability of Aβo or human AD brain TBS-soluble extract to increase calcium in cortical neurons requires mGluR5 and PrPC. The calcium increase in neurons may occur by the IP3 pathway and also by regulation of NMDA-Rs. Fyn activation by Aβo-PrPC is as strong as that by Glu, whereas calcium mobilization appears to be an order of magnitude less effective for Aβo-PrPC than for Glu.