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

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 PrPC-Ln signals. The Ln γ1-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, coimmunoprecipitation, and colocalization experiments showed that group I metabotropic glutamate receptors (mGluR1/5) associate with PrPC. Expressio...