Calcium channel and NMDA receptor activities differentially regulate nuclear C/EBPbeta levels to control neuronal survival.
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.
Marshall
John
J
Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA. john_marshall@brown.edu
Dolan
Bridget M
BM
Garcia
Elizabeth P
EP
Sathe
Suvarna
S
Tang
Xiaoli
X
Mao
Zixu
Z
Blair
Leslie A C
LA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000096:biosynthesis*; D019703:Calcineurin / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D002467:Cell Nucleus / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000502:physiology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D011494:Protein Kinases / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000502:physiology; D017470:Receptors, Glutamate / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000096:biosynthesis*; D014162:Transfection
D022762:CCAAT-Enhancer-Binding Proteins; D015220:Calcium Channels; C497251:Ddit3 protein, rat; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D007334:Insulin-Like Growth Factor I; D011494:Protein Kinases; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517686:Camk4 protein, rat; D019703:Calcineurin