CREB transcriptional activity in neurons is regulated by multiple, calcium-specific phosphorylation events.
The transcription factor CREB mediates diverse responses in the nervous system. It is not known how CREB induces specific patterns of gene expression in response to different extracellular stimuli. We find that Ca(2+) influx into neurons induces CREB phosphorylation at Ser133 and two additional sites, Ser142 and Ser143. While CREB Ser133 phosphorylation is induced by many stimuli, phosphorylation at Ser142 and Ser143 is selectively activated by Ca(2+) influx. The triple phosphorylation of CREB is required for effective Ca(2+) stimulation of CREB-dependent transcription, but the phosphorylation of Ser142 and Ser143, in addition to Ser133, disrupts the interaction of CREB with its cofactor CBP. These results suggest that Ca(2+) influx triggers a specific program of gene expression in neurons by selectively regulating CREB phosphorylation.
Kornhauser
Jon M
JM
Division of Neuroscience, Children's Hospital and Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Cowan
Christopher W
CW
Shaywitz
Adam J
AJ
Dolmetsch
Ricardo E
RE
Griffith
Eric C
EC
Hu
Linda S
LS
Haddad
Chia
C
Xia
Zhengui
Z
Greenberg
Michael E
ME
D000595:Amino Acid Sequence / Q000235:genetics; D050882:CREB-Binding Protein; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D007150:Immunohistochemistry; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D010766:Phosphorylation; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D009687:Nuclear Proteins; D015534:Trans-Activators; D050882:CREB-Binding Protein; D002118:Calcium