期刊
NEURON
卷 39, 期 4, 页码 625-639出版社
CELL PRESS
DOI: 10.1016/S0896-6273(03)00496-3
关键词
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资金
- NCRR NIH HHS [P20 RR 15578] Funding Source: Medline
- NICHD NIH HHS [HD39446] Funding Source: Medline
- NINDS NIH HHS [R01 NS37676, R01 NS39063-01A2] Funding Source: Medline
Insulin-like growth factor-1 (IGF-1) promotes the survival of cerebellar granule neurons by enhancing calcium influx through L-type calcium channels, whereas NMDA receptor-mediated calcium influx can lead to excitotoxic death. Here we demonstrate that L and NMDA receptor channel activities differentially regulate the transcription factor C/EBPbeta to control neuronal survival. Specifically, we show that L channel-dependent calcium influx results in increased CaMKIV activity, which acts to decrease nuclear C/EBPbeta levels. Conversely, NMDA receptor-mediated influx rapidly elevates nuclear C/EBPbeta and induces excitotoxic death via activation of the calcium-dependent phosphatase, calcineurin. Moderate levels of AMPA receptor activity stimulate L channels to improve survival, whereas higher levels stimulate NMDA receptors and reduce neuronal survival, suggesting differential synaptic effects. Finally, N-type calcium channel activity reduces survival, potentially by increasing glutamate release. Together, these results show that the L-type calcium channel-dependent survival and NMDA receptor death pathways converge to regulate nuclear C/EBPbeta levels, which appears to be pivotal in these mechanisms.
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