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https://www.readbyqxmd.com/read/29337043/membrane-permeable-rab27a-is-a-regulator-of-the-acrosome-reaction-role-of-geranylgeranylation-and-guanine-nucleotides
#1
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
https://www.readbyqxmd.com/read/29336505/signalling-transduction-events-involved-in-agonist-induced-pge2-ep4-receptor-externalization-in-cultured-rat-dorsal-root-ganglion-neurons
#2
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
https://www.readbyqxmd.com/read/29322373/epac-is-required-for-exogenous-and-endogenous-stimulation-of-adenosine-a2b-receptor-for-inhibition-of-angiotensin-ii-induced-collagen-synthesis-and-myofibroblast-differentiation
#3
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
https://www.readbyqxmd.com/read/29301606/epac2a-knockout-mice-are-resistant-to-dexamethasone-induced-skeletal-muscle-atrophy-and-short-term-cold-stress
#4
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
https://www.readbyqxmd.com/read/29225130/on-the-g-protein-coupling-selectivity-of-the-native-a2b-adenosine-receptor
#5
Zhan-Guo Gao, Asuka Inoue, Kenneth A Jacobson
A2B adenosine receptor (A2BAR) activation induces Gs-dependent cyclic AMP accumulation. However, A2BAR 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 1321N1 astrocytoma, HEK293, and T24 bladder cancer cells endogenously expressing human A2BAR, 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, A2BAR-mediated ERK1/2 activity occurred via both Gi and Gs, but not Gq/11...
December 7, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29216750/pde-camp-epac-c-ebp-%C3%AE-signaling-cascade-regulates-mitochondria-biogenesis-of-tubular-epithelial-cells-in-renal-fibrosis
#6
Hao Ding, Feng Bai, Hongdi Cao, Jing Xu, Li Fang, JiNing Wu, Qi Yuan, Yang Zhou, Qi Sun, WeiChun He, ChunSun Dai, Ke Zen, Lei Jiang, Junwei Yang
AIM: cAMP is a universal second messenger that plays an important role in intracellular signal transduction. cAMP is synthesized by adenylate cyclases (ACs) from adenosine triphosphate (ATP), and terminated by the phosphodiesterases (PDEs). In the present study, we investigated the role of the cAMP pathway in tubular epithelial cells mitochondrial biogenesis in the pathogenesis of renal fibrosis. RESULTS: We found that the cAMP levels were decreased in fibrotic kidney tissues, and replenishing cAMP could ameliorate tubular atrophy and extracellular matrix deposition...
December 7, 2017: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/29183797/increase-in-ca2-current-by-sustained-camp-levels-enhances-proliferation-rate-in-gh3-cells
#7
Andréia Laura Rodrigues, Marcella Brescia, Andreas Kolshinski, Thaís Helena Moreira, Ryan Cameron, George Bailley, Paulo S L Beirão, Manuela Zaccollo, Jader S Cruz
AIMS: Ca2+ and cAMP are important intracellular modulators. In order to generate intracellular signals with various amplitudes, as well as different temporal and spatial properties, a tightly and precise control of these modulators in intracellular compartments is necessary. The aim of this study was to evaluate the effects of elevated and sustained cAMP levels on voltage-dependent Ca2+ currents and proliferation in pituitary tumor GH3 cells. MAIN METHODS: Effect of long-term exposure to forskolin and dibutyryl-cyclic AMP (dbcAMP) on Ca2+ current density and cell proliferation rate were determined by using the whole-cell patch-clamp technique and real time cell monitoring system...
November 25, 2017: Life Sciences
https://www.readbyqxmd.com/read/29175000/cyclic-nucleotide-signaling-changes-associated-with-normal-aging-and-age-related-diseases-of-the-brain
#8
REVIEW
Michy P Kelly
Deficits in brain function that are associated with aging and age-related diseases benefit very little from currently available therapies, suggesting a better understanding of the underlying molecular mechanisms is needed to develop improved drugs. Here, we review the literature to test the hypothesis that a break down in cyclic nucleotide signaling at the level of synthesis, execution, and/or degradation may contribute to these deficits. A number of findings have been reported in both the human and animal model literature that point to brain region-specific changes in Galphas (a...
January 2018: Cellular Signalling
https://www.readbyqxmd.com/read/29174852/activation-of-epac-alleviates-inflammation-and-vascular-leakage-in-lps-induced-acute-murine-lung-injury
#9
Xuefeng Wang, Shunde Song, Zhengqiang Hu, Zhewen Zhang, Yajun Li, Chunguang Yan, Zigang Li, Huifang Tang
Exchange protein directly activated by cAMP (Epac) is an important molecule in cAMP signal transduction, but the effect of Epac on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is unclear. In this study, we treated in vitro and in vivo models with the Epac activator 8CPT to determine the effect and related mechanisms of Epac. The in vitro results indicate that 8CPT inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) release from mouse macrophages (MH-S), whereas the protein kinase A (PKA) activator 6BnZ has no effect...
November 23, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29158262/the-epac-rap1-pathway-prevents-and-reverses-cytokine-induced-retinal-vascular-permeability
#10
Carla J Ramos, Chengmao Lin, Xuwen Liu, David A Antonetti
Increased retinal vascular permeability contributes to macular edema, a leading cause of vision loss in eye pathologies such as diabetic retinopathy, age-related macular degeneration, and central retinal vein occlusions. Pathological changes in vascular permeability are driven by growth factors such as VEGF and by pro-inflammatory cytokines such as TNF-α. Identifying the pro-barrier mechanisms that block vascular permeability and restore the blood-retinal barrier (BRB) may lead to new therapies. The cAMP-dependent guanine nucleotide exchange factor EPAC promotes exchange of GTP in the small GTPase Rap1...
November 20, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29111327/overexpression-of-exchange-protein-directly-activated-by-camp-1-epac1-attenuates-bladder-cancer-cell-migration
#11
Hirona Ichikawa, Momoe Itsumi, Shunichi Kajioka, Tomoko Maki, Ken Lee, Makoto Tomita, Shoji Yamaoka
Exchange protein directly activated by cAMP (EPAC) is a mediator of a cAMP signaling pathway that is independent of protein kinase A. EPAC has two isoforms (EPAC1 and EPAC2) and is a cAMP-dependent guanine nucleotide exchange factor for the small GTPases, Rap1 and Rap2. Recent studies suggest that EPAC1 has both positive and negative influences on cancer and is involved in cell proliferation, apoptosis, migration and metastasis. We report that EPAC1 and EPAC2 expression levels were significantly lower in bladder cancer tissue than in normal bladder tissue...
October 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29108990/laminin-1-induces-endocytosis-of-67kda-laminin-receptor-and-protects-neuroscreen-1-cells-against-death-induced-by-serum-withdrawal
#12
Rayudu Gopalakrishna, Usha Gundimeda, Sarah Zhou, Helena Bui, Andrew Davis, Thomas McNeill, William Mack
Although the function of laminin in the basement membrane is known, the function of soluble "neuronal" laminin is unknown. Since laminin is neuroprotective, we determined whether the soluble laminin-1 induces signaling for neuroprotection via its 67KDa laminin-1 receptor (67LR). Treatment of Neuroscreen-1 (NS-1) cells with laminin-1 or YIGSR peptide, which corresponds to a sequence in laminin-1 β1 chain that binds to 67LR, induced a decrease in the cell-surface expression of 67LR and caused its internalization...
November 8, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29100797/structure-activity-relationships-of-2-substituted-phenyl-n-phenyl-2-oxoacetohydrazonoyl-cyanides-as-novel-antagonists-of-exchange-proteins-directly-activated-by-camp-epacs
#13
Zhiqing Liu, Yingmin Zhu, Haiying Chen, Pingyuan Wang, Fang C Mei, Na Ye, Xiaodong Cheng, Jia Zhou
Exchange proteins directly activated by cAMP (EPACs) are critical cAMP-dependent signaling pathway mediators that play important roles in cancer, diabetes, heart failure, inflammations, infections, neurological disorders and other human diseases. EPAC specific modulators are urgently needed to explore EPAC's physiological function, mechanism of action and therapeutic applications. On the basis of a previously identified EPAC specific inhibitor hit ESI-09, herein we have designed and synthesized a novel series of 2-substituted phenyl-N-phenyl-2-oxoacetohydrazonoyl cyanides as potent EPAC inhibitors...
December 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29037982/early-effects-of-epac-depend-on-the-fine-tuning-of-the-sarcoplasmic-reticulum-ca-2-handling-in-cardiomyocytes
#14
N Lezcano, J I E Mariángelo, L Vittone, X H T Wehrens, M Said, C Mundiña-Weilenmann
In cardiac muscle, signaling through cAMP governs many fundamental cellular functions, including contractility, relaxation and automatism. cAMP cascade leads to the activation of the classic protein kinase A but also to the stimulation of the recently discovered exchange protein directly activated by cAMP (Epac). The role of Epac in the regulation of intracellular Ca(2+) homeostasis and contractility in cardiac myocytes is still matter of debate. In this study we showed that the selective Epac activator, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate (8-CPT), produced a positive inotropic effect when adult rat cardiac myocytes were stabilized at low [Ca(2+)]o (0...
October 14, 2017: Journal of Molecular and Cellular Cardiology
https://www.readbyqxmd.com/read/29027245/epac-induced-ryanodine-receptor-type-2-activation-inhibits-sodium-currents-in-atrial-and-ventricular-murine-cardiomyocytes
#15
Haseeb Valli, Shiraz Ahmad, Sujan Sriharan, Lydia D Dean, Andrew A Grace, Kamalan Jeevaratnam, Hugh R Matthews, Christopher L-H Huang
Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca(2+) homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na(+) current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na(+) currents...
October 12, 2017: Clinical and Experimental Pharmacology & Physiology
https://www.readbyqxmd.com/read/29023245/education-in-pediatrics-across-the-continuum-epac-first-steps-toward-realizing-the-dream-of-competency-based-education
#16
John S Andrews, James F Bale, Jennifer B Soep, Michele Long, Carol Carraccio, Robert Englander, Deborah Powell
The Education in Pediatrics Across the Continuum (EPAC) Study Group is developing the first competency-based, time-variable progression from undergraduate medical education (UME) to graduate medical education (GME) in the history of medical education in the United States. EPAC, an innovation project sponsored by the Association of American Medical Colleges (AAMC) and supported by the Josiah Macy Jr. Foundation, was developed through a collaboration between 5 medical schools and multiple professional organizations with an interest in undergraduate and graduate medical education...
October 11, 2017: Academic Medicine: Journal of the Association of American Medical Colleges
https://www.readbyqxmd.com/read/29018059/involvement-of-leptin-in-the-molecular-physiology-of-the-placenta
#17
Malena Schanton, Julieta Lorena Maymó, Antonio Pérez-Pérez, Victor Sanchez-Margalet, Cecilia Varone
Leptin is a homeostatic regulator in the placenta where it promotes proliferation, protein synthesis and the expression of tolerogenic maternal response molecules such as HLA-G. Leptin also exerts an anti-apoptotic action in placenta controlling the expression of p53 master cell cycle regulator under different stress conditions. On the other hand, leptin is an integrative target of different placental stimuli. The expression of leptin in placenta is regulated by hCG, insulin, steroids, hypoxia, and many other growth hormones, suggesting that it might have an important endocrine function in the trophoblastic cells...
October 9, 2017: Reproduction: the Official Journal of the Society for the Study of Fertility
https://www.readbyqxmd.com/read/29016851/mutations-causing-acrodysostosis-2-facilitate-activation-of-phosphodiesterase-4d3
#18
Claire Briet, Arrate Pereda, Catherine Le Stunff, Emmanuelle Motte, Juan de Dios Garcia-Diaz, Guiomar Perez de Nanclares, Nicolas Dumaz, Caroline Silve
Type 2 acrodysostosis (ACRDYS2), a rare developmental skeletal dysplasia characterized by short stature, severe brachydactyly and facial dysostosis, is caused by mutations in the phosphodiesterase (PDE) 4D (PDE4D) gene. Several arguments suggest that the mutations should result in inappropriately increased PDE4D activity, however, no direct evidence supporting this hypothesis has been presented, and the functional consequences of the mutations remain unclear. We evaluated the impact of four different PDE4D mutations causing ACRDYS2 located in different functional domains on the activity of PDE4D3 expressed in Chinese hamster ovary cells...
October 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28987803/long-acting-%C3%AE-2-adrenoreceptor-agonists-suppress-type-1-interferon-expression-in-human-plasmacytoid-dendritic-cells-via-epigenetic-regulation
#19
Chang-Hung Kuo, San-Nan Yang, Yi-Giien Tsai, Chong-Chao Hsieh, Wei-Ting Liao, Li-Chen Chen, Min-Sheng Lee, Hsuan-Fu Kuo, Ching-Hsiung Lin, Chih-Hsing Hung
The combination of inhaled long-acting β2-adrenoreceptor (LABA) and inhaled glucocorticoid (ICS) is a major therapy for asthma. However, the increased risk of infection is still a concern. Plasmacytoid dendritic cells (pDCs) are the predominant cells producing type 1 interferon (IFN) against infection. The effect of LABA/ICS on type 1 IFN expression in human pDCs is unknown. Circulating pDCs were isolated from healthy human subjects and were pretreated with glucocorticoid (GCS), LABA or a cAMP analog, and were stimulated with Toll-like receptor (TLR) agonist CpG (TLR9) or imiquimod (TLR7) in the presence of IL-3...
October 4, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28945820/anthrax-edema-toxin-disrupts-distinct-steps-in-rab11-dependent-junctional-transport
#20
Annabel Guichard, Prashant Jain, Mahtab Moayeri, Ruth Schwartz, Stephen Chin, Lin Zhu, Beatriz Cruz-Moreno, Janet Z Liu, Bernice Aguilar, Andrew Hollands, Stephen H Leppla, Victor Nizet, Ethan Bier
Various bacterial toxins circumvent host defenses through overproduction of cAMP. In a previous study, we showed that edema factor (EF), an adenylate cyclase from Bacillus anthracis, disrupts endocytic recycling mediated by the small GTPase Rab11. As a result, cargo proteins such as cadherins fail to reach inter-cellular junctions. In the present study, we provide further mechanistic dissection of Rab11 inhibition by EF using a combination of Drosophila and mammalian systems. EF blocks Rab11 trafficking after the GTP-loading step, preventing a constitutively active form of Rab11 from delivering cargo vesicles to the plasma membrane...
September 2017: PLoS Pathogens
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