Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin γ1 chain.

The prion protein (PrP^C) is highly expressed in the nervous system, and its abnormal conformer is associated with prion diseases. PrP^C is anchored to cell membranes by glycosylphosphatidylinositol, and transmembrane proteins are likely required for PrP^C-mediated intracellular signaling. Binding of laminin (Ln) to PrP^C modulates neuronal plasticity and memory. We addressed signaling pathways triggered by PrP^C-Ln interaction in order to identify transmembrane proteins involved in the transduction of PrP^CLn signals. The Ln γl-chain peptide, which contains the Ln binding site for PrP^C, induced neuritogenesis through activation of phospholipase C (PLC), Ca²⁺ mobilization from intracellular stores, and protein kinase C and extracellular signal- regulated kinase (ERK1/2) activation in primary cultures of neurons from wild-type, but not PrP^C-null mice. Phage display, coimmimoprecipitation, and colocalization experiments showed that group I metabotropic glutamate receptors (mGluRl/5) associate with PrP^C. Expression of either mGluRl or mGluR5 in HEK293 cells reconstituted the signaling pathways mediated by PrP^C-Ln γ1 peptide interaction. Specific inhibitors of these receptors impaired PrP^C-Ln γ1 peptide-induced signaling and neuritogenesis. These data show that group I mGluRs are involved in the transduction of cellular signals triggered by PrP^C-Ln, and they support the notion that PrP^C participates in the assembly of multiprotein complexes with physiological functions on neurons. [ABSTRACT FROM AUTHOR]