Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin γ1 chain.
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.
Beraldo
Flavio H
FH
Ludwig Institute for Cancer Research, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil.
Arantes
Camila P
CP
Santos
Tiago G
TG
Machado
Cleiton F
CF
Roffe
Martin
M
Hajj
Gláucia N
GN
Lee
Kil S
KS
Magalhães
Ana C
AC
Caetano
Fabiana A
FA
Mancini
Gabriel L
GL
Lopes
Marilene H
MH
Américo
Tatiana A
TA
Magdesian
Margaret H
MH
Ferguson
Stephen S G
SS
Linden
Rafael
R
Prado
Marco A M
MA
Martins
Vilma R
VR
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007797:Laminin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism
D001565:Benzoates; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; D007797:Laminin; D018621:PrPC Proteins; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C089141:laminin gamma 1; C104077:metabotropic glutamate receptor type 1; C079694:alpha-methyl-4-carboxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010738:Type C Phospholipases; D002118:Calcium; D005998:Glycine