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Kazuya Kusama, Kazuhiro Tamura, Hanako Bai, Toshihiro Sakurai, Hirotaka Nishi, Keiichi Isaka, Kazuhiko Imakawa, Mikihiro Yoshie
Protein kinase A (PKA) signalling accompanies elevated intracellular cAMP levels during endometrial stromal cell (ESC) decidualisation. Exchange protein directly activated by cAMP (EPAC), an alternate mediator of cAMP signalling, promotes PKA analogue-induced decidualisation; however, the precise mechanism by which EPAC and PKA co-operatively stimulate decidualisation has not been characterised. To examine the role of CCAAT/enhancer-binding protein (C/EBP) in EPAC- and PKA-mediated decidualisation of primary human ESCs, a reporter plasmid containing the 332bp region upstream from the transcription initiation site of the decidual prolactin (dPRL) gene was generated and the promoter activity was evaluated using a luciferase assay...
May 8, 2018: Reproduction, Fertility, and Development
Ambikaipakan Balasubramaniam, Sulaiman Sheriff, Lou Ann Friend, J Howard James
PDE4-cAMP pathway plays a predominant role in mediating skeletal muscle proteolysis in burn injury. The present investigations to determine the PDE4 isoform(s) involved in this action revealed that burn injury increased the expression of rat skeletal muscle PDE4B mRNA by 6-fold, but had little or no effect on expression of other PDE4 isoforms. These observations led us to study the effects of burn in PDE4B KO-rats. As reported by us previously, burn injury significantly increased EDL muscle total and myofibrillar proteolysis in WT-rats, but there were no significant effects on either total or myofibrillar protein breakdown in EDL muscle of PDE4B KO-rat with burn injury...
April 25, 2018: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Gergő Szanda, Éva Wisniewski, Anikó Rajki, András Spät
We have previously demonstrated in H295R adrenocortical cells that the Ca2+ -dependent production of intramitochondrial cAMP (mt-cAMP) by the matrix soluble adenylyl cyclase (sAC) is associated with enhanced aldosterone production. Now we examined whether mitochondrial sAC and mt-cAMP fine-tune mitochondrial Ca2+ metabolism to support steroidogenesis. Reduction of mt-cAMP formation resulted in decelerated mitochondrial Ca2+ accumulation in intact cells during K+ -induced Ca2+ signalling and also in permeabilised cells exposed to elevated perimitochondrial [Ca2+ ]...
April 16, 2018: Journal of Cell Science
Julie K Allen, Guillermo N Armaiz-Pena, Archana S Nagaraja, Nouara C Sadaoui, Tatiana Ortiz, Robert Dood, Merve Ozcan, Danielle M Herder, Monika Haemerrle, Kshipra M Gharpure, Rajesha Rupaimoole, Rebecca Previs, Sherry Y Wu, Sunila Pradeep, Xiaoyun Xu, Hee Dong Han, Behrouz Zand, Heather J Dalton, Morgan Taylor, Wei Hu, Justin Bottsford-Miller, Myrthala Moreno-Smith, Yu Kang, Lingegowda S Mangala, Cristian Rodriguez-Aguayo, Vasudha Sehgal, Erika L Spaeth, Prahlad T Ram, Stephen Tc Wong, Frank C Marini, Gabriel Lopez-Berestein, Steve W Cole, Susan K Lutgendorf, Mariella diBiasi, Anil K Sood
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feedforward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner...
April 16, 2018: Cancer Research
S L B Oliveira, M G M Oliveira, D C Hipolide
Sleep deprivation is known to affect memory formation, but how it interacts with different memory systems is not completely understood. Adenosine, a homeostatic regulator of sleep that has an increased extracellular concentration during sleep deprivation, is one of the neuromodulators that may be involved in this interaction. The A1 adenosine receptor is involved in both sleep regulation and memory formation. Among other pathways, the A1 receptor decreases cAMP levels in the cytosol and thus also regulates protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) activity...
March 31, 2018: Neurobiology of Learning and Memory
Thomas Pleli, Antonia Mondorf, Nerea Ferreiros, Dominique Thomas, Karel Dvorak, Ricardo M Biondi, Dagmar Meyer Zu Heringdorf, Stefan Zeuzem, Gerd Geisslinger, Herbert Zimmermann, Oliver Waidmann, Albrecht Piiper
BACKGROUND/AIMS: Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear. METHODS: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors...
March 27, 2018: Cellular Physiology and Biochemistry
Xue-Feng Wang, Shun-de Song, Ya-Jun Li, Zheng Qiang Hu, Zhe-Wen Zhang, Chun-Guang Yan, Zi-Gang Li, Hui-Fang Tang
Quercetin (Que) as an abundant flavonol element possesses potent antioxidative properties and has protective effect in lipopolysaccharide (LPS)-induced acute lung injury (ALI), but the specific mechanism is still unclear, so we investigated the effect of Que from in vivo and in vitro studies and the related mechanism of cAMP-PKA/Epac pathway. The results in mice suggested that Que can inhibit the release of inflammatory cytokine, block neutrophil recruitment, and decrease the albumin leakage in dose-dependent manners...
March 22, 2018: Inflammation
Xiaoqun Zhang, Ioannis Mantas, Alexandra Alvarsson, Takashi Yoshitake, Mohammadreza Shariatgorji, Marcela Pereira, Anna Nilsson, Jan Kehr, Per E Andrén, Mark J Millan, Karima Chergui, Per Svenningsson
The trace amine-associated receptor 1 (TAAR1) is expressed by dopaminergic neurons, but the precise influence of trace amines upon their functional activity remains to be fully characterized. Here, we examined the regulation of tyrosine hydroxylase (TH) by tyramine and beta-phenylethylamine (β-PEA) compared to 3-iodothyronamine (T1 AM). Immunoblotting and amperometry were performed in dorsal striatal slices from wild-type (WT) and TAAR1 knockout (KO) mice. T1 AM increased TH phosphorylation at both Ser19 and Ser40 , actions that should promote functional activity of TH...
2018: Frontiers in Pharmacology
William G Robichaux, Xiaodong Cheng
This review focuses on one family of the known cAMP receptors, the exchange proteins directly activated by cAMP (EPACs), also known as the cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs). Although EPAC proteins are fairly new additions to the growing list of cAMP effectors, and relatively "young" in the cAMP discovery timeline, the significance of an EPAC presence in different cell systems is extraordinary. The study of EPACs has considerably expanded the diversity and adaptive nature of cAMP signaling associated with numerous physiological and pathophysiological responses...
April 1, 2018: Physiological Reviews
Mariachiara Zuccarini, Patricia Giuliani, Monica Frinchi, Giuseppa Mudò, Rosa Maria Serio, Natale Belluardo, Silvana Buccella, Marzia Carluccio, Daniele F Condorelli, Francesco Caciagli, Renata Ciccarelli, Patrizia Di Iorio
Mounting evidence suggests that the guanine-based purines stand out as key player in cell metabolism and in several models of neurodegenerative disorders, such as Parkinson's and Alzheimer's diseases. Guanosine (GUO) and guanine (GUA) are extracellular signaling molecules derived from the breakdown of the correspondent nucleotide, GTP, and their intracellular and extracellular levels are regulated by the fine-tuned activity of two major enzymes, purine nucleoside phosphorylase (PNP) and guanine deaminase (GDA)...
2018: Frontiers in Pharmacology
Wenying Wang, Xiaqing Ma, Limin Luo, Min Huang, Jing Dong, Xiaoli Zhang, Wei Jiang, Tao Xu
BACKGROUND AND PURPOSE: The P2X3 receptor is a major receptor in the processing of nociceptive information in dorsal root ganglia. We investigated the role of the P2X3 receptor and the detailed mechanisms underlying chronic morphine-induced analgesic tolerance in rats. EXPERIMENTAL APPROACH: Repeated i.t. morphine treatment was used to induce anti-nociceptive tolerance. The expression of spinal P2X3 receptor, phosphorylated PKCε and exchange factor directly activated by cAMP (Epac) were evaluated...
May 2018: British Journal of Pharmacology
Jiahong Zhong, Hui Yu, Chang Huang, Qiuping Zhong, Yaping Chen, Jinfeng Xie, Zhongzhen Zhou, Jiangping Xu, Haitao Wang
Phosphodiesterase 4 (PDE4) is a promising target for the treatment of Parkinson's disease (PD). However, the underlying mechanism has not yet been well elucidated. Additionally, most of current PDE4 inhibitors produce severe nausea and vomiting response in patients, which limit their clinical application. FCPR16 is a novel PDE4 inhibitor with little emetic potential. In the present study, the neuroprotective effect and underlying mechanism of FCPR16 against cellular apoptosis induced by 1-methyl-4-phenylpyridinium (MPP+ ) were examined in SH-SY5Y cells...
June 2018: Redox Biology
Yoon-Tae Chung, Virginia Pasquinelli, Javier O Jurado, Xisheng Wang, Na Yi, Peter F Barnes, Veronica E Garcia, Buka Samten
cAMP is critical in immune regulation, and Mycobacterium tuberculosis (Mtb) intoxicates macrophages through cAMP secretion. To examine the role of cAMP in the immune response to Mtb infection, we determined cAMP levels in peripheral blood mononuclear cells (PBMC) from tuberculosis patients and the mechanisms for cAMP suppression of T cell IFN-γ production. PBMC from tuberculosis patients contained significantly higher cAMP levels than latent tuberculosis infected subjects (LTBI), with an inverse correlation with Mtb-stimulated IFN-γ production...
February 8, 2018: Journal of Infectious Diseases
Bakhtyar Sepehri, Nematollah Omidikia, Mohsen Kompany-Zareh, Raouf Ghavami
Aims & Scope: In this research, 8 variable selection approaches were used to investigate the effect of variable selection on the predictive power and stability of CoMFA models. MATERIALS & METHODS: Three data sets including 36 EPAC antagonists, 79 CD38 inhibitors and 57 ATAD2 bromodomain inhibitors were modelled by CoMFA. First of all, for all three data sets, CoMFA models with all CoMFA descriptors were created then by applying each variable selection method a new CoMFA model was developed so for each data set, 9 CoMFA models were built...
2018: Combinatorial Chemistry & High Throughput Screening
Naveen Kumar, Peeyush Prasad, Eshna Jash, Megha Saini, Amjad Husain, Aaron Goldman, Seema Sehrawat
Cancer remains a global health problem and approximately 1.7 million new cancer cases are diagnosed every year worldwide. Although diverse molecules are currently being explored as targets for cancer therapy the tumor treatment and therapy is highly tricky. Secondary messengers are important for hormone-mediated signaling pathway. Cyclic AMP (cAMP), a secondary messenger responsible for various physiological processes regulates cell metabolism by activating Protein kinase A (PKA) and by targeting exchange protein directly activated by cAMP (EPAC)...
February 7, 2018: Molecular and Cellular Biochemistry
Marion Laudette, Haoxiao Zuo, Frank Lezoualc'h, Martina Schmidt
Evidence collected over the last ten years indicates that Epac and cAMP scaffold proteins play a critical role in integrating and transducing multiple signaling pathways at the basis of cardiac and lung physiopathology. Some of the deleterious effects of Epac, such as cardiomyocyte hypertrophy and arrhythmia, initially described in vitro, have been confirmed in genetically modified mice for Epac1 and Epac2. Similar recent findings have been collected in the lung. The following sections will describe how Epac and cAMP signalosomes in different subcellular compartments may contribute to cardiac and lung diseases...
February 3, 2018: Journal of Cardiovascular Development and Disease
Kazuya Kusama, Rulan Bai, Kazuhiko Imakawa
In human trophoblast cells, cyclic AMP or its inducer forskolin (FSK) activates two downstream signaling molecules, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), both of which induce syncytialization, cell fusion, and the production of human chorionic gonadotropin (hCG) and progesterone. However, a transcription factor other than GCM1 and molecular mechanisms associated with these events have not been well characterized. To identify novel transcription factors involved in syncytialization of cAMP-stimulated human choriocarcinoma BeWo cells, the microarray analysis was performed with RNAs extracted from PKA- or EPAC-selective cAMP analog-stimulated BeWo cells, from which two up-regulated transcription factors, STAT5 and NR4A3, were found...
June 2018: Journal of Cellular Biochemistry
Hsing-Chuan Tsai, Sharlene Velichko, Shanshan Lee, Reen Wu
Cholera toxin (CT) is a bacterial component that increases intracellular cAMP levels in host cells and suppresses T-cell activation. Recently, CT was reported to induce T helper type 17-skewing dendritic cells and activate interleukin-17A (IL-17A) production in CD4+ T cells through a cAMP-dependent pathway. However, the underlying mechanism by which cAMP regulates IL-17A production in T cells is not completely defined. In this study, we took advantage of a small molecule protein kinase A (PKA) inhibitor (H89) and different cAMP analogues: a PKA-specific activator (N6-benzoyl-adenosine-cAMP), an exchange protein activated by cAMP-specific activator (Rp-8-chlorophenylthio-2'-O-methyl cAMP), and a PKA inhibitor (Rp-8-bromo-cAMP), to elucidate the signalling cascade of cAMP in IL-17A regulation in T cells...
January 27, 2018: Immunology
Yogesh A Sonawane, Yingmin Zhu, Jered C Garrison, Edward L Ezell, Muhammad Zahid, Xiaodong Cheng, Amarnath Natarajan
EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functional groups. The most potent EPAC inhibitor 12a exists as a mixture of inseparable E (major) and Z (minor) rotamers. The rotation about the N -formyl group indeed impacts the activity against EPAC...
November 9, 2017: ACS Medicinal Chemistry Letters
Pooja Singhmar, XiaoJiao Huo, Yan Li, Patrick M Dougherty, Fang Mei, Xiaodong Cheng, Cobi J Heijnen, Annemieke Kavelaars
Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1-/-) male and female mice are protected against paclitaxel-induced mechanical allodynia...
May 2018: Pain
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