Laminin-γ1 chain and stress inducible protein 1 synergistically mediate PrPC-dependent axonal growth via Ca2+ mobilization in dorsal root ganglia neurons

Authors

  • Tiago G. Santos,

    1. International Research Center, A.C. Camargo Hospital, São Paulo, Brazil
    2. National Institute for Translational Neuroscience (CNPq/MCT/FAPESP), São Paulo, Brazil
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  • Flavio H. Beraldo,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada
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  • Glaucia N. M. Hajj,

    1. International Research Center, A.C. Camargo Hospital, São Paulo, Brazil
    2. National Institute for Translational Neuroscience (CNPq/MCT/FAPESP), São Paulo, Brazil
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  • Marilene H. Lopes,

    1. Department of Cell and Developmental Biology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
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  • Martin Roffe,

    1. International Research Center, A.C. Camargo Hospital, São Paulo, Brazil
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  • Fernanda C. S. Lupinacci,

    1. International Research Center, A.C. Camargo Hospital, São Paulo, Brazil
    2. National Institute for Translational Neuroscience (CNPq/MCT/FAPESP), São Paulo, Brazil
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  • Valeriy G. Ostapchenko,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada
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  • Vania F. Prado,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada
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  • Marco A. M. Prado,

    1. Robarts Research Institute, Department of Physiology and Pharmacology, Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada
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  • Vilma R. Martins

    Corresponding author
    1. National Institute for Translational Neuroscience (CNPq/MCT/FAPESP), São Paulo, Brazil
    • International Research Center, A.C. Camargo Hospital, São Paulo, Brazil
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Address correspondence and reprint requests to Dr Vilma R. Martins, International Research Center, A.C. Camargo Hospital, Rua Tagua 440, São Paulo 01508-010 Brazil. E-mail: vmartins@cipe.accamargo.org.br

Abstract

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 cross-talk 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 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 PrPC-null mice. PrPC binding to Ln-γ1 or STI1 led to an increase in intracellular Ca2+ levels via distinct mechanisms: STI1 promoted extracellular Ca2+ 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 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.

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