期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 285, 期 47, 页码 36542-36550出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.157263
关键词
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资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [03-13189-2]
- Programa Institutos Nacionais de Ciencia e Tecnologia, do Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- PrioNet-Canada
- Canadian Institutes for Health Research
- Department of Foreign Affairs and International Trade-Canada
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [03/13189-2] Funding Source: FAPESP
The prion protein (PrPC) is a conserved glycosylphosphatidyl-inositol-anchored cell surface protein expressed by neurons and other cells. Stress-inducible protein 1 (STI1) binds PrPC 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 PrPC-STI1 interaction transduces extracellular signals to the intracellular environment is unknown. We found that in hippocampal neurons, STI1-PrPC engagement induces an increase in intracellular Ca2+ levels. This effect was not detected in PrPC-null neurons or wild-type neurons treated with an STI1 mutant unable to bind PrPC. Using a best candidate approach to test for potential channels involved in Ca2+ influx evoked by STI1-PrPC, we found that alpha-bungarotoxin, a specific inhibitor for alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), was able to block PrPC-STI1-mediated signaling, neuroprotection, and neuritogenesis. Importantly, when alpha 7nAChR was transfected into HEK 293 cells, it formed a functional complex with PrPC and allowed reconstitution of signaling by PrPC-STI1 interaction. These results indicate that STI1 can interact with the PrPC.alpha 7nAChR complex to promote signaling and provide a novel potential target for modulation of the effects of prion protein in neurodegenerative diseases.
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