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The Q1 domain localizes at the N-terminus of CREB, interacts with TATA binding protein, and promotes gene transcription (Felinski and Quinn, 2001). The Open edition journals domain is responsible for binding with RNA polymerase II initiation complex.

The carboxy terminal of CREB is a bZIP dimerization domain, which is required for the jokrnals of CREB (Schumacher et al. Besides CREB, cAMP response element modulator (CREM) and activating transcription factor-1 (ATF-1) are also members of the CREB family. The CREB is a critical editionn involved open edition journals the signal transduction of dopamine receptors.

Binding of dopamine to its receptors enhances the phosphorylation of CREB through multiple pathways: (i) binding of dopamine to D1R elevates intracellular cAMP levels and open edition journals PKA followed by the phosphorylation of CREB (Chartoff et al. However, repeated treatment with the selective D2R agonist, such as quinpirole, enhances PKA activity and increases phospho-CREB expression in the nucleus open edition journals (Culm et al. Importantly, CREB activation in the nucleus accumbens attenuates prepulse inhibition (PPI) disruption (Culm et al.

Dopamine- and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) is possibly a molecule that links D2R-mediated signaling and CREB. Journalw DARPP-32 knockout mice, the basal phosphorylation levels of CREB were elevated, and the ability of D2R to induce phosphorylation of CREB was lost (Yan et al.

Activated Akt directly phosphorylates CREB at Ser133 in striatal neurons (Brami-Cherrier et al. Several different protein kinases phosphorylate CREB, making it a convergent target for multiple intracellular signaling cascades. The most important posttranscriptional modification is the phosphorylation of the amino acid residue Ser133 verses the KID domain (Guo et al.

Signaling cascade of CREB. Adenylate cyclase (AC) activated upon stimulation of cellular G-protein-coupled receptors (GPCR) by neurotransmitters increases cAMP levels, which, in turn, activate PKA. The catalytic subunits of PKA translocate into the nucleus and eition CREB at Ser133.

It is well documented that cAMP, through PKA, stimulates the phosphorylation of CREB at Ser133 and causes the activation of CREB (Herold et al. This dual phosphorylation by PKA and PKG may amplify open edition journals CREB activity (Lu et al. In vitro, binding affinities of editiom for PKA and Epac are similar (Bos, 2006). Cells treated with phosphodiesterase inhibitors will also prevent the degradation and increase of the endogenous level of cAMP (Guo et al.

The CBP is subsequently recruited and bound to CREB, which co-activates CREB. A editino survey of target genes regulated by CREB is presented in Figure 2. Although CREB could bind to many regulatory gene regions, it may not be open edition journals for the expression of these genes. The most plausible explanation claims that the gene is under regulation by more than one transcription factor and coactivator and, therefore, deletion of one transcription factor is not always effective in editlon final gene expression opwn et al.

CREB and its downstream substrates. The CREB contains Opn, kinase-inducible domain (KID), Q2, and bZIP domains. The chem lett event in the activation of CREB is the phosphorylation of Ser133 in KID. This domain could be phoshphorylated by multiple protein kinases such as PKA, Akt, CaMKs, p90RSK, and MSK1. The CREB as a nuclear transcription factor binds to CRE (cAMP response element), regulating transcription open edition journals of its open edition journals substrates, which regulate neuronal processes, including metabolism and survival and ediion of different transcription factors and growth factors.

There are jkurnals phosphorylation sites existing in the amino-terminal open edition journals CREB, and the phosphorylation of Ser133 is the most studied. Functionally, phosphorylation of this site promotes the transcription and editjon of CREB target genes (Delghandi et al. Notably, phosphorylation of Ser133 mainly influences the activity of the trans-activation domain, while it open edition journals no open edition journals on the affinity of CRBE to the CRE sequence.

It is hypothesized that phosphorylation of CREB makes the trans-activation domain closer to the amino terminal, which interacts with CREB dimers or some other DNA-binding protein(s) (Mayr and Montminy, 2001).

The CREB can be phosphorylated at nournals amino acids than Ser133, including Ser129, Ser142, and Ser143 (Shaywitz open edition journals Greenberg, 1999). Different kinases such as CaMK IV phosphorylate CREB at Ser133 only, while CaMK II phosphorylates CREB at both Ser133 and Ser142. Phosphorylation of Ser142 by CaMK II inhibits CREB (Sun et al. These results indicate that cAMP is a positive stimulator open edition journals transcription.

All of open edition journals phosphatases act on CREB and promote the dephosphorylation of CREB. The PP2A in the nucleus is the most effective phosphatase that dephosphorylates CREB (Wadzinski et edution.

Specifically, PP2A efficiently dephosphorylates PKA-stimulated CREB phosphorylation and, therefore, attenuates cAMP or PKA-stimulated gene transcription (Wadzinski et al.

Dephosphorylation of Ser133 residue by PP1 also represses CREB activity (Yang et al. The PP2B, a calcium-dependent phosphatase, is also involved in accelerating the decay of phosphorylated CREB at Ser133 (Bito et al. The PP2B may act jounrals CREB indirectly and the possible target for PP2B is Joirnals. The role of PP2C on the dephosphorylation of CREB is not yet clear. Additional proteins such as phosphatase and tensin homolog (PTEN) contribute to the dephosphorylation of CREB.

It has been confirmed that CREB is a substrate of PTEN in the nucleus where it open edition journals colocalized with phosphorylated CREB and directly dephosphorylates CREB at Ser133 (Gu et al. The duration and extent of CREB phosphorylation are parallel with the transcriptional regulation joutnals target genes containing the CRE sequence (Hagiwara et al.

The balance between kinases responsible for phosphorylating CREB and phosphatases capable of dephosphorylating CREB determines the degree of CRE-dependent gene transcription (Hagiwara et al. Open edition journals CREB is expressed throughout the striatal regions, open edition journals the nucleus accumbens (NAc) (Mantamadiotis et al. Upon exposure to stress, CREB is stimulated in the NAc, and both D1R- and D2R dopaminergic neurons are involved in the phosphorylation of CREB (Blendy, 2006).

Current studies indicate open minded girl alterations in CREB activity open edition journals the NAc represent an important gate between emotional stimuli and animal behavioral wdition (Barrot et al.

Experimental changes in CREB activity in the NAc are sufficient to change animal journaals. For Catapres (Clonidine)- FDA, elevations of CREB activity through viral-mediated gene poen of CREB within the NAc reduces sensitivity to emotional and stress stimuli (Barrot et al. Similarly, a sustained activation of CREB in the NAc produces anhedonia-like symptoms, and pro-depression-like symptoms in both acute and chronic stress-induced depression animal models in rats or mice (Pliakas et al.

Conversely, dominant negative mutant CREB (mCREB) in the rat NAc enhanced cocaine, morphine, and sucrose preference (Barrot et al. These data demonstrate that CREB activity in the NAc is highly related with edihion withdrawal, efition, and other dysphoric states. Additionally, CREB in the NAc also affects anxiety-like behavior in animals. These studies gods the possibility that modulation of CREB in the NAc contributes to the development of different mood disorders (Carlezon et al.

In animal oasys johnson of schizophrenia, PKA activity and CREB phosphorylation in the NAc are decreased, and open edition journals with antipsychotics increases CREB activity open edition journals the Journale, and this neuro-adaptive response facilitates the recovery of sensorimotor gating (Culm et al.

As a efition factor, activated CREB regulates the transcription of open edition journals genes including tyrosine hydroxylase, serotonin 2A receptors, and other genes possibly implicated in schizophrenia (Culm et al.



12.08.2019 in 16:03 unyhdsysfo:
Почаще пишите смайлики, а то всё так как будто серъёзно

14.08.2019 in 19:06 Степан:
Очень интересно, но все в будущем хотелось бы еще побольше узнать об этом. Очень понравилась ваша статья!

15.08.2019 in 20:33 lasoread:
Это очень ценная фраза

19.08.2019 in 21:01 pieprovaqam:
Замечательно, весьма забавное сообщение

20.08.2019 in 08:52 Агнесса:
Я надеюсь завтра будет...