Nuclear calcium signaling controls CREB-mediated gene expression triggered by synaptic activity.
Information storage in the nervous system requires transcription triggered by synaptically evoked calcium signals. It has been suggested that translocation of calmodulin into the nucleus, initiated by submembranous calcium transients, relays synaptic signals to CREB. Here we show that in hippocampal neurons, signaling to CREB can be activated by nuclear calcium alone and does not require import of cytoplasmic proteins into the nucleus. The nucleus is particularly suited to integrate neuronal firing patterns, and specifies the transcriptional outputs through a burst frequency-to-nuclear calcium amplitude conversion. Calcium release from intracellular stores promotes calcium wave propagation into the nucleus, which is critical for CREB-mediated transcription by synaptic NMDA receptors. Pharmacological or genetic modulation of nuclear calcium may directly affect transcription-dependent memory and cognitive functions.
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, England.
G E
GE
Hardingham
F J
FJ
Arnold
H
H
Bading
D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002147:Calmodulin / Q000378:metabolism / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014909:Wheat Germ Agglutinins / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D002147:Calmodulin; D017362:Cyclic AMP Response Element-Binding Protein; D014909:Wheat Germ Agglutinins