cAMP response element-binding protein is activated by Ca2+/calmodulin- as well as cAMP-dependent protein kinase.
In a variety of nerve cells of the brain, action potentials activate gene expression by means of Ca2+ influx. To determine how Ca2+ influx alters gene expression, we have examined the pattern of phosphorylation of a protein that binds to the cAMP response element (CRE). We have found that purified bovine brain CRE-binding protein is a substrate for the Ca2+/calmodulin-dependent kinase II (Cam kinase) as it is for the cAMP-dependent protein kinase (kinase A). Tryptic peptide maps show that the same peptide is phosphorylated in vitro both by kinase A and by Cam kinase. Moreover, in vitro transcription assays using a CRE-containing c-fos promoter indicate that phosphorylation of CRE-binding protein by Cam kinase increases gene transcription. Thus, action potentials in nerve cells and the consequent influx of Ca2+ can activate CRE-binding proteins by means of Cam kinase. This kinase therefore provides a direct second-messenger pathway by which impulse activity at the membrane can influence gene transcription. This has been shown independently by Sheng et al. (Sheng, M., Thomson, M. A. & Greenberg, M. E. (1991) Science, in press), who found that depolarization and Ca2+ influx mediate induction of c-fos in PC12 rat pheochromocytoma cells through phosphorylation of CRE-binding protein. These several findings indicate that CRE-binding protein(s) is a convergence point for synaptic activity acting through kinase A and impulse activity acting through Cam kinase. Together the two kinases could activate transcription in a synergistic manner, which could allow CRE-binding protein to couple short-term to long-term associative forms of synaptic plasticity.
Dash
P K
PK
Howard Hughes Medical Institute, Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, New York, NY 10032.
Karl
K A
KA
Colicos
M A
MA
Prywes
R
R
Kandel
E R
ER
D000818:Animals; D001921:Brain / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002417:Cattle; D002467:Cell Nucleus / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins / Q000302:isolation & purification / Q000378:metabolism*; D006367:HeLa Cells / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D008954:Models, Biological; D010449:Peptide Mapping; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D014158:Transcription, Genetic
D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases