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The prion protein (PrPC) is highly expressed in the nervous system, and its abnormal conformer is associated with prion diseases. PrPC is anchored to cell membranes by glycosylphosphatidylinositol, and transmembrane proteins are likely required for PrPC-mediated intracellular signaling. Binding of laminin (Ln) to PrPC modulates neuronal plasticity and memory. We addressed signaling pathways triggered by PrPC-Ln interaction in order to identify transmembrane proteins involved in the transduction of PrPCLn signals. The Ln γl-chain peptide, which contains the Ln binding site for PrPC, 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 PrPC-null mice. Phage display, coimmimoprecipitation, and colocalization experiments showed that group I metabotropic glutamate receptors (mGluRl/5) associate with PrPC. Expression of either mGluRl or mGluR5 in HEK293 cells reconstituted the signaling pathways mediated by PrPC-Ln γ1 peptide interaction. Specific inhibitors of these receptors impaired PrPC-Ln γ1 peptide-induced signaling and neuritogenesis. These data show that group I mGluRs are involved in the transduction of cellular signals triggered by PrPC-Ln, and they support the notion that PrPC participates in the assembly of multiprotein complexes with physiological functions on neurons. [ABSTRACT FROM AUTHOR]