Role of alpha7 nicotinic acetylcholine receptor in calcium signaling induced by prion protein interaction with stress-inducible protein 1.
The prion protein (PrP(C)) is a conserved glycosylphosphatidylinositol-anchored cell surface protein expressed by neurons and other cells. Stress-inducible protein 1 (STI1) binds PrP(C) extracellularly, and this activated signaling complex promotes neuronal differentiation and neuroprotection via the extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP-dependent protein kinase 1 (PKA) pathways. ... However, the mechanism by which the PrP(C)-STI1 interaction transduces extracellular signals to the intracellular environment is unknown. We found that in hippocampal neurons, STI1-PrP(C) engagement induces an increase in intracellular Ca(2+) levels. This effect was not detected in PrP(C)-null neurons or wild-type neurons treated with an STI1 mutant unable to bind PrP(C). Using a best candidate approach to test for potential channels involved in Ca(2+) influx evoked by STI1-PrP(C), we found that ?-bungarotoxin, a specific inhibitor for ?7 nicotinic acetylcholine receptor (?7nAChR), was able to block PrP(C)-STI1-mediated signaling, neuroprotection, and neuritogenesis. Importantly, when ?7nAChR was transfected into HEK 293 cells, it formed a functional complex with PrP(C) and allowed reconstitution of signaling by PrP(C)-STI1 interaction. These results indicate that STI1 can interact with the PrP(C)ยท?7nAChR complex to promote signaling and provide a novel potential target for modulation of the effects of prion protein in neurodegenerative diseases.
Mesh Terms:
Animals, Apoptosis, Blotting, Western, Calcium Signaling, Cell Proliferation, Cells, Cultured, Embryo, Mammalian, Female, Heat-Shock Proteins, Hippocampus, Humans, Immunoprecipitation, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 3, Neurons, PrPC Proteins, Protein Binding, RNA, Messenger, Receptors, Nicotinic, Recombinant Proteins, Reverse Transcriptase Polymerase Chain Reaction, alpha7 Nicotinic Acetylcholine Receptor
Animals, Apoptosis, Blotting, Western, Calcium Signaling, Cell Proliferation, Cells, Cultured, Embryo, Mammalian, Female, Heat-Shock Proteins, Hippocampus, Humans, Immunoprecipitation, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 3, Neurons, PrPC Proteins, Protein Binding, RNA, Messenger, Receptors, Nicotinic, Recombinant Proteins, Reverse Transcriptase Polymerase Chain Reaction, alpha7 Nicotinic Acetylcholine Receptor
J. Biol. Chem.
Date: Nov. 19, 2010
PubMed ID: 20837487
View in: Pubmed Google Scholar
Download Curated Data For This Publication
222052
Switch View:
- Interactions 1