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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 (P2X3R) is a major receptor in the processing of nociceptive information in dorsal root ganglia (DRGs). We investigated the role of the P2X3R and the detailed mechanisms underlying chronic morphine-induced analgesic tolerance in rats. EXPERIMENTAL APPROACHES: Under isoflurane inhalation anaesthesia, intrathecal catheters were implanted in male Sprague-Dawley rats. Repeated intrathecal (i.t.) morphine treatment was used to induce anti-nociceptive tolerance...
March 3, 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...
February 14, 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
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. 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 model were built. Obtained results show noisy and uninformative variables affect CoMFA results...
February 12, 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...
January 29, 2018: Journal of Cellular Biochemistry
Hsing-Chuan Tsa, 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 Th17-skewing dendritic cells and activate IL-17A production in CD4+ T cells via 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 PKA inhibitor (H89) and different cAMP analogs: a PKA-specific activator (N6-Benzoyl-adenosine-cAMP), a EPAC-specific activator (Rp-8-Chlorophenylthio-2'-O-methyl cAMP), and a PKA inhibitor (Rp-8-Bromo-cAMP), to elucidate the signaling 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...
January 23, 2018: Pain
Graeme Barker, Euan Parnell, Boy van Basten, Hanna Buist, David R Adams, Stephen J Yarwood
The cyclic 3',5'-adenosine monophosphate (cAMP) sensor enzyme, EPAC1, is a candidate drug target in vascular endothelial cells (VECs) due to its ability to attenuate proinflammatory cytokine signalling normally associated with cardiovascular diseases (CVDs), including atherosclerosis. This is through the EPAC1-dependent induction of the suppressor of cytokine signalling gene, SOCS3, which targets inflammatory signalling proteins for ubiquitinylation and destruction by the proteosome. Given this important role for the EPAC1/SOCS3 signalling axis, we have used high throughput screening (HTS) to identify small molecule EPAC1 regulators and have recently isolated the first known non-cyclic nucleotide (NCN) EPAC1 agonist, I942...
December 5, 2017: Journal of Cardiovascular Development and Disease
Carlos Alberto Arcaro, Renata Pires Assis, Neusa Maria Zanon, Sílvia Paula-Gomes, Luiz C C Navegantes, Isis Carmo Kettelhut, Iguatemy Lourenço Brunetti, Amanda Martins Baviera
Advances in the knowledge of the mechanisms controlling protein breakdown in skeletal muscles have allowed the exploration of new options for treating muscle wasting conditions. Pentoxifylline (PTX), a nonselective phosphodiesterase (PDE) inhibitor, attenuates the loss of muscle mass during catabolic conditions, mainly via inhibiting protein breakdown. The aim of this study was to explore the mechanisms by which PTX inhibits proteolysis in the soleus and extensor digitorum longus (EDL) muscles of streptozotocin-induced diabetic rats...
December 14, 2017: Journal of Applied Physiology
Matías A Bustos, Ornella Lucchesi, María C Ruete, Claudia N Tomes
The acrosome reaction is the regulated exocytosis of mammalian sperm's single secretory granule, essential for fertilization. It relies on small GTPases, the cAMP binding protein Epac, and the SNARE complex, among other components. Here, we describe a novel tool to investigate Rab27-related signaling pathways: a hybrid recombinant protein consisting of human Rab27A fused to TAT, a cell penetrating peptide. With this tool, we aimed to unravel the connection between Rab3, Rab27 and Rap1 in sperm exocytosis and to deepen our understanding about how isoprenylation and guanine nucleotides influence the behaviour of Rab27 in exocytosis...
January 11, 2018: Cellular Signalling
W Ma, B St-Jacques
BACKGROUND: Prostaglandin E2 (PGE2) enriched in inflamed tissues contributes to chronic pain by sensitizing nociceptive dorsal root ganglion (DRG) neurons (nociceptors). Of four PGE2 receptors (EP1-4), EP4 plays a major role in PGE2-induced nociceptor sensitization. We have previously reported that PGE2 or EP4 agonists stimulated EP4 externalization in cultured DRG neurons and this event contributes to nociceptor sensitization. However, the signalling transduction events governing this event remain unknown...
January 16, 2018: European Journal of Pain: EJP
Sarawuth Phosri, Kwanchai Bunrukchai, Warisara Parichatikanond, Vilasinee H Sato, Supachoke Mangmool
Angiotensin II (Ang II) plays an important role on the pathogenesis of cardiac fibrosis. Prolong and overstimulation of angiotensin II type 1 receptor with Ang II-induced collagen synthesis and myofibroblast differentiation in cardiac fibroblasts, leading to cardiac fibrosis. Although adenosine and its analogues are known to have cardioprotective effects, the mechanistic by which adenosine A2 receptors (A2Rs) inhibit Ang II-induced cardiac fibrosis is not clearly understood. In the present study, we examined the effects of exogenous adenosine and endogenous adenosine on Ang II-induced collagen and myofibroblast differentiation determined by α-smooth muscle action (α-SMA) overexpression and their underlying signal transduction...
January 10, 2018: Purinergic Signalling
Seung-Eun Song, Su-Kyung Shin, So-Young Park, Il-Seon Hwang, Seung-Soon Im, Jae-Hoon Bae, Myung-Sook Choi, Dae-Kyu Song
Exchange protein directly activated by cAMP (Epac) 2a-knockout (KO) mice exhibit accelerated diet-induced obesity and are resistant to leptin-mediated adipostatic signaling from the hypothalamus to adipose tissue, with sustained food intake. However, the impact of Epac2a deficiency on hypothalamic regulation of sympathetic nervous activity (SNA) has not been elucidated. This study was performed to elucidate the response of Epac2a-KO mice to dexamethasone-induced muscle atrophy and acute cold stress. Compared to age-matched wild-type mice, Epac2a-KO mice showed higher energy expenditures and expression of myogenin and uncoupling protein-1 in skeletal muscle (SM) and brown adipose tissue (BAT), respectively...
January 5, 2018: BMB Reports
Zhan-Guo Gao, Asuka Inoue, Kenneth A Jacobson
A2B adenosine receptor (A2B AR) activation induces Gs-dependent cyclic AMP accumulation. However, A2B AR G protein-coupling to other signaling events, e.g. ERK1/2 and calcium, is not well documented. We explored Gi, Gq/11 and Gs coupling in 1321 N1 astrocytoma, HEK293, and T24 bladder cancer cells endogenously expressing human A2B AR, using NECA or nonnucleoside BAY60-6583 as agonist, selective Gi, Gs and Gq/11 blockers, and CRISPR/Cas9-based Gq- and Gs-null HEK293 cells. In HEK293 cells, A2B AR-mediated ERK1/2 activity occurred via both Gi and Gs, but not Gq/11...
December 7, 2017: Biochemical Pharmacology
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