1. Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin γ1 chain.
- Author
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Beraldo FH, Arantes CP, Santos TG, Machado CF, Roffe M, Hajj GN, Lee KS, Magalhães AC, Caetano FA, Mancini GL, Lopes MH, Américo TA, Magdesian MH, Ferguson SS, Linden R, Prado MA, and Martins VR
- Subjects
- Animals, Benzoates pharmacology, Calcium metabolism, Cells, Cultured, Female, Glycine analogs & derivatives, Glycine pharmacology, HEK293 Cells, Humans, Immunoblotting, Laminin genetics, Laminin pharmacology, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Neurites metabolism, Neurons cytology, Neurons drug effects, Neurons metabolism, PrPC Proteins genetics, Protein Binding, Pyridines pharmacology, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, Metabotropic Glutamate genetics, Type C Phospholipases metabolism, Laminin metabolism, Neurites physiology, PrPC Proteins metabolism, Receptors, Metabotropic Glutamate metabolism, Signal Transduction physiology
- Abstract
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(C)-Ln signals. The Ln γ1-chain peptide, which contains the Ln binding site for PrP(C), induced neuritogenesis through activation of phospholipase C (PLC), Ca(2+) 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, coimmunoprecipitation, and colocalization experiments showed that group I metabotropic glutamate receptors (mGluR1/5) associate with PrP(C). Expression of either mGluR1 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.
- Published
- 2011
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