A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons.
Prevailing views of neurotrophin action hold that the transcription factor CREB is constitutively bound to target genes with transcriptional activation occurring via CREB phosphorylation. However, we report that within several CRE-containing genes, CREB is not constitutively bound. Upon exposure of neurons to brain-derived neurotrophic factor (BDNF), CREB becomes rapidly bound to DNA coincident with phosphorylation at its transcriptional regulatory site, Ser133. This inducible CREB-DNA binding is independent of CREB Ser133 phosphorylation and is not affected by inhibition of the ERK or PI3K signaling pathways. Instead, BDNF regulates CREB binding by initiating a nitric oxide-dependent signaling pathway that leads to S-nitrosylation of nuclear proteins that associate with CREB target genes. Pharmacological manipulation of neurons in vitro and analysis of mice lacking neuronal nitric oxide synthase (nNOS) suggest that NO mediates BDNF and activity-dependent expression of CREB target genes. Thus, in conjunction with CREB phosphorylation, the NO pathway controls CREB-DNA binding and CRE-mediated gene expression.
Riccio
Antonella
A
Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21201, USA. a.riccio@ucl.ac.uk
Alvania
Rebecca S
RS
Lonze
Bonnie E
BE
Ramanan
Narendrakumar
N
Kim
Taeho
T
Huang
Yunfei
Y
Dawson
Ted M
TM
Snyder
Solomon H
SH
Ginty
David D
DD
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D052248:Nitric Oxide Synthase Type I / Q000172:deficiency / Q000235:genetics; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D009435:Synaptic Transmission
D019208:Brain-Derived Neurotrophic Factor; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009569:Nitric Oxide; D012694:Serine; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse