CREB at the Crossroads of Activity-Dependent Regulation of Nervous System Development and Function

Belgacem, Yesser Hadj; Borodinsky, Laura N.

doi:10.1007/978-3-319-62817-2_2

Cited by 37 publications

(37 citation statements)

References 86 publications

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“…D 1 receptors are the most abundant dopaminergic receptor in CNS and their functional crosstalk with D 2 receptor is well documented 11,37,38 . D 1 receptor activate adenylyl cyclase (AC), which in turn regulate intracellular cAMP levels leading to PKA activation and CREB phosphorylation 39–41 . Our data have shown that selective D 1 receptor activation upregulated ADAMTS2 expression alongside a rapid phosphorylation of CREB and ERK proteins, which resulted in CREB-mediated transcriptional activity as detected by using specific reporter assays (Fig.…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

et al. 2019

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A better understanding of the molecular mechanisms that participate in the development and clinical manifestations of schizophrenia can lead to improve our ability to diagnose and treat this disease. Previous data strongly associated the levels of deregulated ADAMTS2 expression in peripheral blood mononuclear cells (PBMCs) from patients at first episode of psychosis (up) as well as in clinical responders to treatment with antipsychotic drugs (down). In this current work, we performed an independent validation of such data and studied the mechanisms implicated in the control of ADAMTS2 gene expression. Using a new cohort of drug-naïve schizophrenia patients with clinical follow-up, we confirmed that the expression of ADAMTS2 was highly upregulated in PBMCs at the onset (drug-naïve patients) and downregulated, in clinical responders, after treatment with antipsychotics. Mechanistically, ADAMTS2 expression was activated by dopaminergic signalling (D1-class receptors) and downstream by cAMP/CREB and mitogen-activated protein kinase (MAPK)/ERK signalling. Incubation with antipsychotic drugs and selective PKA and MEK inhibitors abrogated D1-mediated activation of ADAMTS2 in neuronal-like cells. Thus, D1 receptors signalling towards CREB activation might participate in the onset and clinical responses to therapy in schizophrenia patients, by controlling ADAMTS2 expression and activity. The unbiased investigation of molecular mechanisms triggered by antipsychotic drugs may provide a new landscape of novel targets potentially associated with clinical efficacy.

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Section: Discussionmentioning

confidence: 99%

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

et al. 2019

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“…Recently, an elegant study has demonstrated that activation of the cyclic adenosine monophosphate (cAMP) response element binding (CREB) protein plays an important role in poststroke recovery from motor deficits (Caracciolo et al, 2018 ). This might also be of functional relevance for a role of DA in recovery from stroke as it can regulate CREB activity (Hyman et al, 1995 ; Gershon et al, 2007 ; Belgacem and Borodinsky, 2017 ). Additionally, DA appears to play a role in sprouting of spared neurons, and support of new born neurons through potentially modulation of growth factor expression.…”

Section: Potential Mechanisms Of Action Of Da-enhancing Drugsmentioning

confidence: 99%

The Intersection of Central Dopamine System and Stroke: Potential Avenues Aiming at Enhancement of Motor Recovery

Gower

Tiberi

2018

Front. Synaptic Neurosci.

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Dopamine, a major neurotransmitter, plays a role in a wide range of brain sensorimotor functions. Parkinson's disease and schizophrenia are two major human neuropsychiatric disorders typically associated with dysfunctional dopamine activity levels, which can be alleviated through the druggability of the dopaminergic systems. Meanwhile, several studies suggest that optimal brain dopamine activity levels are also significantly impacted in other serious neurological conditions, notably stroke, but this has yet to be fully appreciated at both basic and clinical research levels. This is of utmost importance as there is a need for better treatments to improve recovery from stroke. Here, we discuss the state of knowledge regarding the modulation of dopaminergic systems following stroke, and the use of dopamine boosting therapies in animal stroke models to improve stroke recovery. Indeed, studies in animals and humans show stroke leads to changes in dopamine functioning. Moreover, evidence from animal stroke models suggests stimulation of dopamine receptors may be a promising therapeutic approach for enhancing motor recovery from stroke. With respect to the latter, we discuss the evidence for several possible receptor-linked mechanisms by which improved motor recovery may be mediated. One avenue of particular promise is the subtype-selective stimulation of dopamine receptors in conjunction with physical therapy. However, results from clinical trials so far have been more mixed due to a number of potential reasons including, targeting of the wrong patient populations and use of drugs which modulate a wide array of receptors. Notwithstanding these issues, it is hoped that future research endeavors will assist in the development of more refined dopaminergic therapeutic approaches to enhance stroke recovery.

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“…Interestingly, an intracellular calcium chelator BAPTA‐AM could effectively eliminate the regulation of DJ‐1 deficiency on CREB1 activity (Figure a), suggesting that CaMKs may be the major pathway involving in the regulation of CREB by DJ‐1. Many studies suggest that CaMKs are a type of major kinases to activate CREB1 activity (Belgacem & Borodinsky, ; Mayr & Montminy, ). Among them, CaMKIV activity is essential for directly phosphorylating CREB1 at Ser133 and contributes to transactivate specific genes that contain CRE sequences (Bito, Deisseroth, & Tsien, ; Sun, Enslen, Myung, & Maurer, ; Westphal, Anderson, Means, & Wadzinski, ).…”

Section: Resultsmentioning

confidence: 99%

DJ‐1 regulates tyrosine hydroxylase expression through CaMKKβ/CaMKIV/CREB1 pathway in vitro and in vivo

Wang

Hao

et al. 2019

Journal Cellular Physiology

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Lack of dopamine production and neurodegeneration of dopaminergic neurons in the substantia nigra are considered as the major characteristics of Parkinson's disease, a prevalent movement disorder worldwide. DJ-1 mutation leading to loss of its protein functions is a genetic factor of PD. In this study, our results illustrated that DJ-1 can directly interact with Ca 2+ /calmodulin-dependent protein kinase kinase β (CaMKKβ) and modifies the cAMP-responsive element binding protein 1 (CREB1) activity, thus regulates tyrosine hydroxylase (TH) expression. In Dj-1 knockout mouse substantia nigra, the levels of TH and the phosphorylation of CREB1 Ser133 are significantly decreased. Moreover, Dj-1 deficiency suppresses the phosphorylation of CaMKIV (Thr196/200) and CREB1 (Ser133), subsequently inhibits TH expression in vitro.Furthermore, Knockdown of Creb1 abolishes the effects of DJ-1 on TH regulation.Our data reveal a novel pathway in which DJ-1 regulates CaMKKβ/CaMKIV/CREB1 activities to facilitate TH expression.

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CREB at the Crossroads of Activity-Dependent Regulation of Nervous System Development and Function

Cited by 37 publications

References 86 publications

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

Dopaminergic control of ADAMTS2 expression through cAMP/CREB and ERK: molecular effects of antipsychotics

The Intersection of Central Dopamine System and Stroke: Potential Avenues Aiming at Enhancement of Motor Recovery

DJ‐1 regulates tyrosine hydroxylase expression through CaMKKβ/CaMKIV/CREB1 pathway in vitro and in vivo

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