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Prion protein (PrPc) is a cell surface glycoprotein that is abundantly expressed in nervous system. The elucidation of the PrPc interactome network and its significance on neural physiology is crucial to understanding neurodegenerative events associated with prion and Alzheimer's diseases. PrPc co-opts stress inducible protein 1/alpha7 nicotinic acetylcholine receptor (STI1/α7nAChR) or laminin/Type I metabotropic glutamate receptors (mGluR1/5) to modulate hippocampal neuronal survival and differentiation. However, potential crosstalk between these protein complexes and their role in peripheral neurons has never been addressed. To explore this issue, we investigated PrPc-mediated axonogenesis in peripheral neurons in response to STI1 and Iaminin-γ1 chain-derived peptide (Ln-γ1). STI1 and Ln-γ1 promoted robust axonogenesis in wild-type neurons, whereas no effect was observed in neurons from PrPc-null mice. PrPc binding to Ln- y1 or STI1 led to an increase in intracellular Caz+ levels via distinct mechanisms: STI1 promoted extracellular Ca2+ influx, and Ln-y1 released calcium from intracellular stores. Both effects depend on phospholipase C activation, which is modulated by mGluR1/5 for Ln-γ1, but depends on, C-type transient receptor potential (TRPC) channels rather than cx7nAChR for STI1. Treatment of neurons with suboptimal concentrations of both ligands led to synergistic actions on PrPc-mediated calcium response and axonogenesis. This effect was likely mediated by simultaneous binding of the two ligands to PrPc. These results suggest a role for PrPc as an organizer of diverse multiprotein complexes, triggering specific signaling pathways and promoting axonogenesis In the peripheral nervous system. [ABSTRACT FROM AUTHOR]

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]

Prion protein (PrP(C)) is a cell surface glycoprotein that is abundantly expressed in nervous system. The elucidation of the PrP(C) interactome network and its significance on neural physiology is crucial to understanding neurodegenerative events associated with prion and Alzheimer's diseases. PrP(C) co-opts stress inducible protein 1/alpha7 nicotinic acetylcholine receptor (STI1/α7nAChR) or laminin/Type I metabotropic glutamate receptors (mGluR1/5) to modulate hippocampal neuronal survival and differentiation. However, potential cross-talk between these protein complexes and their role in peripheral neurons has never been addressed. To explore this issue, we investigated PrP(C)-mediated axonogenesis in peripheral neurons in response to STI1 and laminin-γ1 chain-derived peptide (Ln-γ1). STI1 and Ln-γ1 promoted robust axonogenesis in wild-type neurons, whereas no effect was observed in neurons from PrP(C) -null mice. PrP(C) binding to Ln-γ1 or STI1 led to an increase in intracellular Ca(2+) levels via distinct mechanisms: STI1 promoted extracellular Ca(2+) influx, and Ln-γ1 released calcium from intracellular stores. Both effects depend on phospholipase C activation, which is modulated by mGluR1/5 for Ln-γ1, but depends on, C-type transient receptor potential (TRPC) channels rather than α7nAChR for STI1. Treatment of neurons with suboptimal concentrations of both ligands led to synergistic actions on PrP(C)-mediated calcium response and axonogenesis. This effect was likely mediated by simultaneous binding of the two ligands to PrP(C). These results suggest a role for PrP(C) as an organizer of diverse multiprotein complexes, triggering specific signaling pathways and promoting axonogenesis in the peripheral nervous system., (© 2012 International Society for Neurochemistry.)