CREB: a Ca 2+ -Regulated Transcription Factor Phosphorylated by Calmodulin-Dependent Kinases

The mechanism by which Ca 2+ mediates gene induction in response to membrane depolarization was investigated. The adenosine 3′,5′-monophosphate (cAMP) response element-binding protein (CREB) was shown to function as a Ca 2+ -regulated transcription factor and as a substrate for depolarization-activated Ca 2+ -calmodulin-dependent protein kinases (CaM kinases) I and II. CREB residue Ser 133 was the major site of phosphorylation by the CaM kinases in vitro and of phosphorylation after membrane depolarization in vivo. Mutation of Ser 133 impaired the ability of CREB to respond to Ca 2+ . These results suggest that CaM kinases may transduce electrical signals to the nucleus and that CREB functions to integrate Ca 2+ and cAMP signals.