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CREB Signaling in Neurons

The process of consolidating a new memory and the dynamic complexity of information processing within neuronal networks is greatly increased by activity-dependent changes in gene expression within individual neurons. A key paradigm of such regulation is the activation of the nuclear transcription factor CREB (cAMP responsive element binding protein)and its family members the ATF (activating transcription factor) and CREM (cAMP response element modulator). CREB can form homodimers or heterodimers with other members of the ATF family. Heterodimerization of CREB decreases its stability and CRE (cAMP Responsive Element) binding affinity. Activation of CREB leads to a variety of biological responses such as neuronal excitation, long-term memory formation, neural cell proliferation, and opiate tolerance...

CREB Signaling in Neurons

Pathway Summary

The process of consolidating a new memory and the dynamic complexity of information processing within neuronal networks is greatly increased by activity-dependent changes in gene expression within individual neurons. A key paradigm of such regulation is the activation of the nuclear transcription factor CREB (cAMP responsive element binding protein)and its family members the ATF (activating transcription factor) and CREM (cAMP response element modulator). CREB can form homodimers or heterodimers with other members of the ATF family. Heterodimerization of CREB decreases its stability and CRE (cAMP Responsive Element) binding affinity. Activation of CREB leads to a variety of biological responses such as neuronal excitation, long-term memory formation, neural cell proliferation, and opiate tolerance.The crucial event in the activation of CREB is the phosphorylation of Ser133 in its kinase-inducible domain (KID). Ser133 phosphorylation of CREB can be caused by kinases like PKA, CaMK and p70S6K in response to electrical activity, growth factors, neurotransmitter or hormone action on GPCR, or by neurotrophin effects on RTKs. In the nucleus, activated CREB results in the recruitment of the transcriptional coactivators CBP and p300. Elk1 is a part of a Ternary Complex Factor (TCF) that activates RSKs and binds SRF to the SRE. Phosphorylation of Elk1 increases its transcriptional ability to form ternary complexes with SRF at the SRE in the promoter region of many genes, such as c-Fos. CBP/p300 stimulates gene expression by interacting with components of the general transcriptional machinery or by promoting the acetylation of specific lysine residues in nucleosomes located near transcriptionally active promoters thus creating access to the gene for the basal transcriptional machinery. The basal transcriptional machinery includes TBP, TFIIB, and RNA Pol-II. The accumulation of cAMP in response to activation of GPCR also induces PLC-γ that catalyzes the formation of DAG, a PKC activator through phosphatidylinositols (PI). PI3K is responsible for activation of Akt/PKB which directly or indirectly affects CREB.In the presynaptic terminal, metabotropic Glutamate Receptors Group-I (GLUR) augment glutamate release via interaction of PKC and PKA whereas Group-II/III Receptors inhibit glutamate release. In the postsynaptic striatal neurons, group-I receptors increase PKC activity as well as intracellular Ca2+ levels from internal store via PLC/DAG and PI/IP3 pathways, respectively. Activated PKC induces an increase in extracellular Ca2+ influx through phosphorylation of iGluR. Elevation of Ca2+ through calcium channels upregulates Ca2+-dependent CaMK-II/ ERK1/2 signaling cascades resulting in CREB and Elk1 phosphorylation. In contrast, group-II/III receptors suppress the Ca2+ cascades by inhibiting AC coupling to GPCRs such as dopamine receptors.The cAMP/CREB signaling pathway has been strongly implicated in cell proliferation and survival, glucose homeostasis, spermatogenesis, circadian rhythms and the synaptic plasticity that is associated with a variety of complex forms of memory including spatial and social learning indicating that CREB may be a universal modulator of processes required for memory formation

CREB Signaling in Neurons Genes list

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