Cyclic CREB

CREB stands for cyclic-AMP response element (CRE) binding protein and is a transcription factor. When phosphorylated by cyclic AMP- and cyclic GMP-dependent Protein Kinases or other protein kinases it binds to gene promoters that contain a specific binding site. After binding, the respective transcription activity is modulated. 

A sequence stretch 300 base pairs upstream of the transcriptional start site suffices for most of the transcriptional regulation of the IL-6 gene (Fig. 1). Within this sequence stretch several transcription factors find their specific recognition sites. In 5 to 3 direction, AP-1, CREB, C/EBP 3/NF-IL6, SP-1 and NF-kB can bind to the promoter followed by TATA and its TATA binding protein TBP. Most enhancer factors become active in response to one or several different stimuli and the active factors can trigger transcription individually or in concert. For example, AP-1 is active upon cellular stress, or upon stimuli that tell cells to proliferate CREB becomes also active if cells experience growth signals, but also upon elevation of intracellular levels of cyclic adenosine monophosphate (cAMP), which occurs upon stimulation if so called hormone-activated G protein-coupled receptors. 

Another type of cardiomyopathy is termed dilated cardiomyopathy. Mutations in the genes encoding dystrophin, muscle LIM protein (so called because it was found to contain a cysteine-tich domain originally detected in three proteins Lin-II, Isl-1, and Mec-3), and the cyclic response-element binding ptotein (CREB) have been implicated in the causation of this condition. The first two proteins help organize the conttactile ap-params of cardiac muscle cells, and CREB is involved... 

Noradrenaline acts on three types of receptor. The ai receptors mediate the main excitatory effects of noradrenaline upon wake-active neurons in the dorsal raphe, basal forebrain, and elsewhere (Vandermaelen Aghajanian, 1983 Nicoll, 1988 Fort et al., 1995 Brown et al., 2002). The a2 receptors mediate inhibitory effects of noradrenaline, e.g. on noradrenaline neurons themselves and on cholinergic brainstem neurons (Williams et al., 1985 Williams Reiner, 1993). The (3-receptors modulate neurons in a more subtle fashion, increasing excitability via blockade of afterhyperpolarizations in hippocampal and cortical neurons (Haas Konnerth, 1983). Activation of (3-receptors also promotes synaptic plasticity via activation of the cyclic-AMP-dependent kinase (PKA) and cyclic AMP response element binding protein (CREB) signal transduction pathway (Stanton Sarvey, 1987 Cirelli et al., 1996). 

The H2 receptor is the second class of HA receptors. This is another G-protein-coupled receptor but, unlike the Hi receptor, the H2 receptor is coupled to adenylyl cyclase via the GTP-binding Gs protein (Hill et ah, 1997). Encoded by an intronless gene and located on human chromosome 5, the H2 receptor is made up of c. 358 amino acids (Gantz et ah, 1991 Traiffort et ah, 1995). Activation of the H2 receptor causes an accumulation of cAMP and activation of protein kinase A that eventually leads to the activation of cyclic-AMP-response element (CRE)-binding protein (CREB) (Hill et ah, 1997). In neurons, the H2 receptor mediates its excitatory effects by blocking the Ca2+-dependent K+ channel (Haas Konnerth, 1983). 

CREB cyclic AMP response element binding protein... 

FIGURE 35-6 Examples of apoptotic and antiapoptotic mechanisms that act on or within different subcellular compartments. CBP, Ca2+ binding protein CREB, cyclic AMP response element binding protein HSP, heat shock protein IP3, inositol 1,4,5-trisphosphate ROS, reactive oxygen species. 

Antidepressant treatment has, in recent studies, been shown to upregulate the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) cascade and expression of BDNF [59]. This upregulation of CREB and BDNF raises the possibility that antidepressant treatment could oppose the cell death pathway, possibly via increased expression of the oncogene Bcl-2. Studies are necessary to determine if antidepressant treatment increases Bcl-2 expression. Increased expression of Bcl-2 in brain and cultured cells, and inhibition of apoptosis of cultured cerebellar granule neurons have been reported with lithium treatment [57]. Mice lacking the BDNF TrkB receptor fail to show behavioral and neurogenic responses to antidepressants. 

An example of specific transcriptional control is cyclic AMP-dependent regulation of genes that have a cyclic AMP response element (CRE) through the action of the transcription factor CREB (cyclic AMP response element binding protein. Figure 12-5). 

BNST, bed nucleus of the stria terminalis CREB, cyclic AMP response element-binding protein CRH, corticotrophin-releasing hormone CS, conditioned stimuH GABA, y-aminobutyric acid GCC, voltage-gated calcium channels NE, norepinephrine NMDA, iST-methyl-D-aspartate PAG, periaqueductal gray. 

Meyer, T.E. and Habener, J.E (1993) Cyclic adenosine 3, 5 -monophosphate response element-binding protein (CREB) and related transcription-activating deoxyribonucleic acid-binding proteins. Endocr Rev 14 269-290. 

FIGURE 2—14. Multiple transcription factors are represented here, including active and inactive forms, estradiol (E2), cyclic AMP response binding element (CREB), and the leucine zipper formed by Fos and Jun. 

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