Lithium enhances CRTC oligomer formation and the interaction between the CREB coactivators CRTC and CBP — Implications for CREB-dependent gene transcription

Heinrich, Annette; Heyde, A.; Böer, Ulrike; Phu, Do Thanh; Tzvetkov, Mladen V.; Oetjen, Elke

doi:10.1016/j.cellsig.2012.09.016

Cited by 18 publications

(11 citation statements)

References 45 publications

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“…Heinrich et al . () recently reported that the KIX domain of CBP increased CRTC1 binding to phosphorylated CREB, which indicated that CBP could be recruited by phosphorylated CREB and, then, enhance the binding activity of CRTC1 to CREB to activate transcription. This finding suggests that the GABA‐induced activation of Bdnf‐pIV may be controlled by interactions between CREB, CBP, and CRTC1, which could, in turn, be controlled by ERK/MAPK, CaMK, and CN.…”

Section: Discussionmentioning

confidence: 94%

Excitatory GABA induces BDNF transcription via CRTC1 and phosphorylated CREB‐related pathways in immature cortical cells

Fukuchi

Kirikoshi

Mori

et al. 2014

Journal of Neurochemistry

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Although the excitatory action of GABA has been shown to activate the expression of brain-derived neurotrophic factor (BDNF), its molecular mechanisms remain unclear. Using cultured rat cortical cells, we here demonstrated that GABA induced Bdnf mRNA expression mainly via L-type voltagedependent Ca 2+ channels (L-VDCC) at the early stage and inhibited it at the late stage of the culture, which corresponded to the excitatory and inhibitory states of cortical cells. The excitatory GABA-induced Bdnf mRNA expression was controlled by multiple Ca 2+ signaling pathways including Ca 2+ / calmodulin-dependent protein kinase (CaMK), mitogen-activated protein kinase (MAPK) and calcineurin (CN). The Bdnfpromoter IV (Bdnf-pIV) was activated by GABA, mainly via cAMP-response element (CRE)/CREB, and this was prevented by the over-expression of a dominant negative CREB. The nuclear translocation of CREB-regulated transcriptional coactivator 1 (CRTC1) was selectively induced by the GABA-induced CN pathway to activate Bdnf-pIV. On the other hand, GABA-induced Gal4-CREB-dependent transcription, which was controlled by multiple Ca 2+ signaling pathways, was prevented when the serine at position 133 of Gal4-CREB was mutated to alanine. Taken together, the excitatory action of GABA transcriptionally activated Bdnf expression through the combination of nuclear-localized CRTC1 and phosphorylated CREB in immature cortical cells, and may be the molecular mechanisms underlying Bdnf expression to control neuronal development.

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Section: Discussionmentioning

confidence: 94%

Excitatory GABA induces BDNF transcription via CRTC1 and phosphorylated CREB‐related pathways in immature cortical cells

Fukuchi

Kirikoshi

Mori

et al. 2014

Journal of Neurochemistry

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“…22 , 36 , 37 , 38 In a previous study, we showed an Aβ-mediated impairment in CRTC1-dependent gene transcription that was reflected by reduced CRTC1 nuclear translocation, reduced CRTC1 occupancy at synaptic plasticity-associated gene promoters and reduced transcription of plasticity-associated genes in AD transgenic rats. 22 As it has been reported that higher concentrations of lithium enhances CRTC1 oligomer formation as well as the interaction between CREB co-activating factors CRTC1 and CREB-binding protein, 39 , 40 , 41 we tested whether NP03 lithium microdoses could reverse the Aβ-driven impairment in CRTC1 promoter occupancy. Thus, consistent with our previous report, 22 we found that in AD transgenic rats, genomic promoter occupancy was significantly reduced for Bdnf iv (brain-derived neurotrophic factor) ( Figure 3f ).…”

Section: Resultsmentioning

confidence: 99%

BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

et al. 2017

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Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer’s disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.

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“…Moreover, an in vitro cell‐based assay such as ours provides a buffer to effects of medication that might be measured in direct assays of lymphocytes, brain, or spinal fluid. For example, lithium has been shown to enhance the association between CREB and its coactivator regulated transcription coactivator (CRTC) (Heinrich et al ., ), and such an effect is unlikely in a cellular assay conducted in vitro after weeks in culture.…”

Section: Discussionmentioning

confidence: 99%

Human cellular differences in cAMP ‐ CREB signaling correlate with light‐dependent melatonin suppression and bipolar disorder

Gaspar

Werken

Johansson

et al. 2014

Eur J of Neuroscience

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Various lines of evidence suggest a mechanistic role for altered cAMP-CREB (cAMP response element - binding protein) signaling in depressive and affective disorders. However, the establishment and validation of human inter-individual differences in this and other major signaling pathways has proven difficult. Here, we describe a novel lentiviral methodology to investigate signaling variation over long periods of time directly in human primary fibroblasts. On a cellular level, this method showed surprisingly large inter-individual differences in three major signaling pathways in human subjects that nevertheless correlated with cellular measures of genome-wide transcription and drug toxicity. We next validated this method by establishing a likely role for cAMP-mediated signaling in a human neuroendocrine response to light - the light-dependent suppression of the circadian hormone melatonin - that shows wide inter-individual differences of unknown origin in vivo. Finally, we show an overall greater magnitude of cellular CREB signaling in individuals with bipolar disorder, suggesting a possible role for this signaling pathway in susceptibility to mental disease. Overall, our results suggest that genetic differences in major signaling pathways can be reliably detected with sensitive viral-based reporter profiling, and that these differences can be conserved across tissues and be predictive of physiology and disease susceptibility.

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Lithium enhances CRTC oligomer formation and the interaction between the CREB coactivators CRTC and CBP — Implications for CREB-dependent gene transcription

Cited by 18 publications

References 45 publications

Excitatory GABA induces BDNF transcription via CRTC1 and phosphorylated CREB‐related pathways in immature cortical cells

Excitatory GABA induces BDNF transcription via CRTC1 and phosphorylated CREB‐related pathways in immature cortical cells

BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology

Human cellular differences in cAMP ‐ CREB signaling correlate with light‐dependent melatonin suppression and bipolar disorder

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