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

Abstract

The mechanism by which Ca2+ 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 Ser133 was the major site of phosphorylation by the CaM kinases in vitro and of phosphorylation after membrane depolarization in vivo. Mutation of Ser133 impaired the ability of CREB to respond to Ca2+. These results suggest that CaM kinases may transduce electrical signals to the nucleus and that CREB functions to integrate Ca2+ and cAMP signals.

N-methyl-d-aspartate receptor independent changes in expression of polysialic acid-neural cell adhesion molecule despite blockade of homosynaptic long-term potentiation and heterosynaptic long-term depression in the awake freely behaving rat dentate gyrus

“…The expression of PSA is regulated by the polysialyltransferase PST and STX mainly at the transcription level but also in post-translational ways (reviewed in Angata and Fukuda, 2003). Since the transcription of at least one of the polysialyltransferases (STX) has been shown to be activated by the cAMP response element binding protein (CREB) (Nakagawa et al, 2002) and that CREB is activated by calcium entry through both NMDA-receptors and L-type voltage-dependent calcium channels (VDCC) (Sheng et al, 1991;Deisseroth et al, 1996;Hardingham et al, 2001), it is probable that HFS induced the activation of CREB through L-type VDCC alone (in the presence of CPP) and thereby increased the STX transcription level. Entry of calcium in this way is also likely to activate post-translational regulatory pathways such as, for instance, the activation of the protein kinase C (PKC), which has been shown to regulate the polysialyltransferases activity in chick ciliary ganglion (Bruses et al, 1995;Bruses and Rutishauser, 1998).…”

Cross-talk in signal transduction: Ras-dependent induction of cAMP-responsive transcriptional repressor ICER by nerve growth factor

“…We discuss the possible physiological implications of these results. miny, 1989;Dash et al, 1991;Sheng et al, 1991;de Groot et al, 1993de Groot et al, , 1994Ginty et al, 1994). In particular, activation of transduction pathways independent from cAMP may also result in CREB phosphorylation, as for instance in PC12 cells upon NGF treatment (Ginty et al, 1994).…”

Altered Regulation of CREB by Chronic Antidepressant Administration in the Brain of Transgenic Mice with Impaired Glucocorticoid Receptor Function

“…In addition, the complexity of the regulation of CREB becomes evident when the elevated numbers of signal transduction pathways that converge onto this transcription factor are considered (Bito et al 1996). CREB is phosphorylated by many kinases other than PKA, including CAMKIV (Ca ϩϩ -calmodulin kinase IV), PKC (protein kinase Ca ϩϩ dependent), CKI and CKII (casein kinases I and II) (Sheng et al 1991;Shaywitz and Greenberg 1999). Also, an abundance of factors as diverse as peptide hormones, neurotransmitter systems, neuro-protective agents, and growth factors, such as BDNF and NGF regulate CREB gene expression and activation.…”