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Regulation of Airway Smooth Muscle Proliferation by β2-Adrenoceptor Agonists
Published in Alastair G. Stewart, AIRWAY WALL REMODELLING in ASTHMA, 2020
Alastair G. Stewart, Paul R. Tomlinson, Leslie Schachte
A number of genes contain sequences in the promoter regions called cAMP response elements (CREs) which are activated by CRE-binding protein (CREB). Increases in cAMP may cause activation and nuclear translocation of PKA, which is then able to phosphorylate CREB, increasing its transcriptional activity.147 CREB binds to a nuclear protein called CREB-binding protein (CBP)148 which is also bound by the phosphorylated (active) form of Jun. It has been suggested that limiting levels of CBP may cause competition between CREB and Jun, resulting in mutual inhibition.149 Given the importance of Jun in activating mitogen-sensitive genes (see Figure 4), it is plausible that cAMP could inhibit cell proliferation by phosphorylated CREB sequestering the available CBP and, therefore, inhibiting the transcriptional activity of Jun complexes.
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Increased cAMP levels activate PKA, which acts upon several targets, including cAMP response element binding protein (CREB) and DARPP-32 (32-kDa dopamine and cAMP-regulated phosphoprotein). PKA is a tetramer, composed of two regulatory (R) and two catalytic (C) subunits. Binding of four cAMP molecules to the R subunit promotes conformational changes that result in the dissociation of the C monomers. Upon ATP binding, the C monomers become activated and can phosphorylate cytoplasmic and nuclear proteins that contain the appropriate consensus sequence. CREB is a transcription factor that is activated by PKA-induced Ser133 phosphorylation and regulates the transcription of numerous genes [50]. DARPP-32 is a multifunctional phosphoprotein with a protein phosphatase 1 (PPI) inhibitory function. DARPP-32 becomes activated upon PKA- and cyclin-dependent kinase 5-induced Thr34 phosphorylation [51]. As discussed in Chapters 11 and 12, DARPP-32 play a critical role in tumorigenesis and is overexpressed in breast, prostate, colon, and stomach cancers.
Drugs of Abuse and Addiction
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Aarushi Singh
In assorted regions of brain responsible for addiction, the CREB protein gets activated by the drugs and most prominently in the nucleus accumbens. This CREB activation represents a negative feedback mechanism as it reduces the satisfying effects of the drug by actually lessening the sensitivity of an individual and mediates dependence on drug at the time of drug withdrawal (Robison and Nestler, 2012; Nestler, 2013). This negative reinforcement leads to self-administering of drugs by the people and probably relapse. This action of CREB in the regions of amygdala and hippocampus is contemplated as a vital factor in behavioral memory. For example, in case of opioid, the initiation of dynorphin (peptides of opioid) expression in NAc neurons is regulated via CREB (Shaw-Lutchman et al., 2002; Shaw-Lutchman et al., 2003; Robison and Nestler, 2012; Nestler, 2013). CREB is associated with the increasing dynorphin activation of κ-opioid receptors present on the DA neurons which lie in the VTA region and henceforth suppressing dopamine transmission to NAc and thus impairing reward related behavior. Target genes for CREB are known only in some drugs, about its mantle in other drugs of abuse still remains undisclosed (Shaw-Lutchman et al., 2002; Shaw-Lutchman et al., 2003; Carlezon et al., 2005; Edwards et al., 2007; Altarejos and Montminy, 2011).
Mitochondrial biogenesis alteration in arsenic-induced carcinogenesis and its therapeutic interventions
Published in Toxin Reviews, 2023
Kshirod Bihari Sathua, Rakesh Kumar Singh
cAMP response element binding protein (CREB) is an omnipresent nuclear transcription factor which acts both directly and indirectly. In response to increase in energy demands, cAMP signaling pathways activated mediated by CREB. The mitochondrial function is directly regulated by CREB, and is indirectly regulated via PGC-1α resulting into cell proliferation, differentiation, homeostasis, and survival. CREB acts as proto-oncogene in different tumor types and involved in progression of carcinogenesis (Sapio et al. 2020, Herzig et al. 2001). Though CREB activation in arsenicosis is well known, but its involvement in carcinogenesis is less explored (Qu et al.2016, Srivastava et al.2018). Even the interlinking of the molecular events between CREB, mitochondrial biogenesis, and homeostasis concerning to chronic arsenic-induced carcinogenesis is yet to be resolved.
Quetiapine attenuates the acquisition of morphine-induced conditioned place preference and reduces ERK phosphorylation in the hippocampus and cerebral cortex
Published in The American Journal of Drug and Alcohol Abuse, 2022
Ali Khezri, Mahdieh Sadat Mohsenzadeh, Elnaz Mirzayan, Nima Bagherpasand, Mohammad Fathi, Khalil Abnous, Mohsen Imenshahidi, Soghra Mehri, Hossein Hosseinzadeh
Phosphorylation of ERK can lead to the activation of CREB in brain cells. The changes in CREB function may mediate the rewarding effects of morphine. In this regard, it has been reported that CREB phosphorylation in rat hippocampus, PFC, and nucleus accumbens was increased after morphine-induced conditioning (9,18,21). In contrast, antagonism of AMPA/Kainate (55) or NMDA (56) glutamate receptor decreased CREB phosphorylation and inhibited morphine-induced CPP. Our results did not show alterations in total protein and phospho-protein expression of CREB in the hippocampus and cerebral cortex of rats receiving morphine, compared to the control group. These results align with a previous study demonstrating that morphine administration had no effects on CREB or p-CREB (1). A possible explanation for these different results could be due to the short conditioning phase in this study. Moreover, the elevated p-ERK levels may not be high enough to activate CREB protein changes.
Effects of Hibiscus sabdariffa calyces on spatial memory and hippocampal expression of BDNF in ovariectomized rats
Published in Nutritional Neuroscience, 2022
Gerardo Lorenzana-Martínez, Anne Santerre, Isaac Andrade-González, Jacinto Bañuelos-Pineda
BDNF is expressed throughout the brain, especially in the neurons of the hippocampus. The BDNF gene follows a rapid expression pattern in response to a diversity of stimuli. BDNF protein is excreted either as a mature protein or in an immature form (Pro-BDNF). Each protein isoform binds to a specific membrane receptor: the P75 receptor for Pro-BDNF, which is associated with pro-apoptotic or survival signals through different cascades such as JNK or NF-kB, respectively [51], and the Trk-B receptor for the mature BDNF isoform. Mature BDNF may form dimers and suffer glycosylation as well as glycosulfation [52]. The Trk-B-BDNF complex activates several secondary messengers such as PI3, Akt, PLC, and ERK, which activate signaling pathways that converge to affect CREB signaling. CREB is a transcription factor for many genes involved in memory and synaptic plasticity [53]. The Trk-B-BDNF complex is also involved in neuron morphologic changes and long-term potentiation (LTP) processes as well as neuron survival [54,55]. Trk-B-BDNF also plays an important role in learning and memory formation through the regulation of neuroplasticity [56,57]. Many factors are involved in BDNF signaling; in the present work, we focused our attention on BDNF itself [58]. Specifically, we looked at the effect of ovariectomy and the ingestion of HSE on BDNF expression because of the role of this neurotrophin in growth, survival, and neuron differentiation [59]. Particularly, BDNF has been reported to counteract the physiopathology of Alzheimer’s, Huntington’s and Parkinson’s diseases [60].