Synaptic activity induces signalling to CREB without increasing global levels of cAMP in hippocampal neurons.
Nuclear calcium signals associated with electrical activation of neurons can control the activity of the transcription factor cAMP-response element binding protein (CREB). Yet, cAMP is thought to be the key messenger that links synaptic activity to the regulation of CREB-mediated transcription. It is generally assumed that synaptic activity increases the intracellular levels of cAMP; this causes activation of the cAMP-dependent protein kinase (PKA) that regulates CREB-mediated transcription either directly or through controlling nuclear signalling of the MAP kinases/extracellular signal-regulated kinases (ERK1/2) pathway. Here we show that, in hippocampal neurons, synaptic activity failed to increase global levels of cAMP that would be required for the cAMP-PKA system to induce nuclear events. Even near-continuous bursting of action potentials, giving rise to large nuclear calcium signals and robust CREB-dependent transcription, left global intracellular levels of cAMP unchanged. These results suggest that the cAMP-PKA system does not function as the transducer of synaptic signals to the nucleus. They indicate that the known inhibitory effects of blockers of PKA on gene expression and long-lasting plasticity triggered by calcium entry reflect a gating function of basal activity of PKA that renders neurons permissive for nuclear calcium-regulated, CREB/CBP-dependent gene expression.
Pokorska
Anna
A
MRC Laboratory of Molecular Biology, Division of Neurobiology, Hills Road, Cambridge, UK.
Vanhoutte
Peter
P
Arnold
Fiona J L
FJ
Silvagno
Francesca
F
Hardingham
Giles E
GE
Bading
Hilmar
H
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D017362:Cyclic AMP Response Element-Binding Protein; D018756:GABA Antagonists; D026902:Potassium Channel Blockers; D005576:Colforsin; D018698:Glutamic Acid; D011189:Potassium Chloride; D000242:Cyclic AMP; D002118:Calcium