title: Laminin-γ1 chain and stress inducible protein 1 synergistically mediate PrPC-dependent axonal growth via Ca2+ mobilization in dorsal root ganglia neurons.
abstract: 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.
authors.affiliation: International Research Center, A.C. Camargo Hospital, São Paulo, Brazil.
authors.forename: Tiago G
authors.initials: TG
authors.lastname: Santos
authors.forename: Flavio H
authors.initials: FH
authors.lastname: Beraldo
authors.forename: Glaucia N M
authors.initials: GN
authors.lastname: Hajj
authors.forename: Marilene H
authors.initials: MH
authors.lastname: Lopes
authors.forename: Martin
authors.initials: M
authors.lastname: Roffe
authors.forename: Fernanda C S
authors.initials: FC
authors.lastname: Lupinacci
authors.forename: Valeriy G
authors.initials: VG
authors.lastname: Ostapchenko
authors.forename: Vania F
authors.initials: VF
authors.lastname: Prado
authors.forename: Marco A M
authors.initials: MA
authors.lastname: Prado
authors.forename: Vilma R
authors.initials: VR
authors.lastname: Martins
mesh_terms: D000818:Animals; D001369:Axons / Q000737:chemistry / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology; D045604:Extracellular Fluid / Q000737:chemistry / Q000502:physiology; D005727:Ganglia, Spinal / Q000737:chemistry / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000502:physiology*; D007424:Intracellular Fluid / Q000737:chemistry / Q000378:metabolism; D007797:Laminin / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018621:PrPC Proteins / Q000502:physiology*; D061251:Primary Cell Culture; D011485:Protein Binding / Q000502:physiology; D020239:Receptor Cross-Talk / Q000502:physiology*; D011984:Sensory Receptor Cells / Q000737:chemistry / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D006360:Heat-Shock Proteins; D007797:Laminin; D018621:PrPC Proteins; C489791:Stip1 protein, mouse; C089141:laminin gamma 1