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Adenylyl cyclases

Xiaofen Ruan, Tiejun Chen, Xiaolong Wang, Yiping Li
Suxiao Jiuxin Pill (SX), a traditional Chinese medicine compound consisting primarily of tetramethylpyrazine and borneol, has been reported to protect against ischemic heart disease. However, the effects of SX on mitochondrial injury and gene expression in various signaling pathways are unclear. The aim of the present study was to investigate the effects of SX on mitochondrial injury and to screen the expression of genes potentially altered by SX using a cell culture model of ischemic injury. Simulated ischemia was established by culturing HL-1 cardiomyocytes in Dulbecco's modified Eagle medium without glucose or serum in a hypoxic chamber containing 95% N2 and 5% CO2 for 24 h...
October 2017: Experimental and Therapeutic Medicine
Wenling Chen, Helena S Ennes, James A McRoberts, Juan Carlos Marvizon
The interaction between NMDA receptors and μ-opioid receptors in primary afferent terminals was studied by using NMDA to induce substance P release, measured as neurokinin 1 receptor internalization. In rat spinal cord slices, the μ-opioid receptor agonists morphine, DAMGO and endomorphin-2 inhibited NMDA-induced substance P release, whereas the antagonist CTAP right-shifted the concentration response of DAMGO. In vivo, substance P release induced by intrathecal NMDA after priming with BDNF was inhibited by DAMGO...
October 14, 2017: Neuropharmacology
Qian Wang, Patricia Cobo-Stark, Vishal Patel, Stefan Somlo, Pyung-Lim Han, Peter Igarashi
Cyclic AMP promotes cyst growth in polycystic kidney disease (PKD) by stimulating cell proliferation and fluid secretion. Previously, we showed that the primary cilium of renal epithelial cells contains a cAMP regulatory complex comprising adenylyl cyclases 5 and 6 (AC5/6), polycystin-2, A-kinase anchoring protein 150, protein kinase A, and phosphodiesterase 4C. In Kif3a mutant cells that lack primary cilia, the formation of this regulatory complex is disrupted and cAMP levels are increased. Inhibition of AC5 reduces cAMP levels in Kif3a mutant cells, suggesting that AC5 may mediate the increase in cAMP in PKD...
October 14, 2017: Kidney International
Jason Burch, Siavash Mashayekh, Dennis D Wykoff, Catherine Leimkuhler Grimes
The dimorphic yeast Candida albicans is the most common pathologic fungus found in humans. While this species is normally commensal, a morphological switch from budding yeast to filamentous hyphae allows the fungi to invade epithelial cells and cause infections. The phenotypic change is controlled by the adenylyl cyclase, Cyr1. Interestingly, this protein contains a leucine-rich repeat (LRR) domain, which is commonly found in innate immune receptors from plants and animals. A functional and pure LRR domain was obtained in high yields from E...
October 17, 2017: ACS Infectious Diseases
Gislaine Francieli da Silva, Mariana Ferreira Dos Anjos, Lilian Wunsch Rocha, Luiz Felipe Gomes Rebello Ferreira, Dorimar Serafim Stiz, Rogério Corrêa, Jose Roberto Santin, Valdir Cechinel Filho, Marcelo Zaldini Hernandes, Nara Lins Meira Quintão
The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor)...
October 12, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Melissa W Li, Arthur C Sletten, Jiyeon Lee, Kelly D Pyles, Scot J Matkovich, Daniel S Ory, Jean E Schaffer
Small nucleolar RNAs (snoRNAs) guide chemical modifications of ribosomal and small nuclear RNAs, functions that are carried out in the nucleus. While most snoRNAs reside in the nucleolus, a growing body of evidence indicates that snoRNAs are also present in the cytoplasm and that snoRNAs move between the nucleus and cytoplasm by a mechanism that is regulated by lipotoxic and oxidative stress. Here, in a genome-wide shRNA-based screen we identified nuclear export factor 3 (NXF3) as a transporter that alters the nucleocytoplasmic distribution of box C/D snoRNAs from the ribosomal protein L13a (Rpl13a) locus...
October 11, 2017: Journal of Biological Chemistry
Nitin Singh Chouhan, Krithika Mohan, Aurnab Ghose
Social rituals, like male-male aggression in Drosophila, are often stereotyped and the component behavioral patterns modular. The likelihood of transition from one behavioral pattern to another is malleable by experience and confers flexibility to the behavioral repertoire. Experience-dependent modification of innate aggressive behavior in flies alters fighting strategies during fights and establishes dominant-subordinate relationships. Dominance hierarchies resulting from agonistic encounters are consolidated to longer lasting social status-dependent behavioral modifications resulting in a robust loser effect...
October 9, 2017: Journal of Experimental Biology
Kristian R von Schalburg, Brent E Gowen, Jong S Leong, Eric B Rondeau, William S Davidson, Ben F Koop
Much progress has been made regarding our understanding of aromatase regulation, estrogen synthesis partitioning and communication between the germinal and somatic compartments of the differentiating gonad. We now know that most of the enzymatic and signaling apparatus required for steroidogenesis is endogenously expressed within germ cells. However, less is known about the expression and localization of steroidogenic components within mature spermatozoa. We have assembled a sperm library presenting 197,015 putative transcripts...
October 5, 2017: Histochemistry and Cell Biology
Michael P Hayes, Monica Soto-Velasquez, C Andrew Fowler, Val J Watts, David L Roman
Adenylyl cyclases (AC) catalyze the formation of cyclic AMP (cAMP) from ATP and are involved in a number of disease states, making them attractive potential drug targets. AC8, in particular, has been implicated in several neurological disorders. While development of small molecule AC inhibitors has generated some chemical leads, the lack of inhibitor specificity among AC family members has limited the identification of successful drug candidates. Therefore, finding alternative novel methods to suppress AC activity are needed...
October 16, 2017: ACS Chemical Neuroscience
Roberta Benedetto, Jiraporn Ousingsawat, Podchanart Wanitchakool, Yong Zhang, Michael J Holtzman, Margarida Amaral, Jason R Rock, Rainer Schreiber, Karl Kunzelmann
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is the secretory chloride/bicarbonate channel in airways and intestine that is activated through ATP binding and phosphorylation by protein kinase A, but fails to operate in cystic fibrosis (CF). TMEM16A (also known as anoctamin 1, ANO1) is thought to function as the Ca(2+) activated secretory chloride channel independent of CFTR. Here we report that tissue specific knockout of the TMEM16A gene in mouse intestine and airways not only eliminates Ca(2+)-activated Cl(-) currents, but unexpectedly also abrogates CFTR-mediated Cl(-) secretion and completely abolishes cAMP-activated whole cell currents...
September 29, 2017: Scientific Reports
Jung-Chin Chang, Simei Go, Arthur J Verhoeven, Ulrich Beuers, Ronald P J Oude Elferink
Primary biliary cholangitis (PBC) is a chronic fibrosing cholangiopathy characterized by an autoimmune stereotype and defective biliary bicarbonate secretion due to down-regulation of anion exchanger 2 (AE2). Despite the autoimmune features, immunosuppressants are ineffective while two bile acid-based therapies (ursodeoxycholic acid and obeticholic acid) have been shown to improve biochemical and histological features of cholestasis and long-term prognosis. However, the etiology and pathogenesis of PBC is largely unknown...
September 26, 2017: Biochimica et Biophysica Acta
Lara Faggi, Andrea Giustina, Giovanni Tulipano
For a few years we have been investigating AMP-activated protein kinase (AMPK) as a target for drug therapy of GH-secreting pituitary adenomas. Aim of this study was to investigate the direct effects of metformin, which causes AMPK activation in different cell types, on rat pituitary adenoma cell growth and on related cell signalling pathways. Our results suggest that metformin can exert a growth-inhibitory activity in rat pituitary tumor cells mediated by AMPK activation, although multiple mechanisms are most likely involved...
September 27, 2017: Molecular and Cellular Endocrinology
Irina V Kravchenko, Vladimir A Furalyov, Vladimir O Popov
Myofibrillar proteins titin and myomesin stimulated myoblast proliferation as determined by MTT-test and labelled thymidine incorporation in the DNA. Specific Fn type III and Ig-like domains of these proteins were able to exert mitogenic effects as well. Proliferative effect of Fn type III domains was highly sensitive to inhibition of Ca(2+)/calmodulin dependent protein kinase, whereas the effect of Ig-like domains showed greater sensitivity to the inhibition of adenylyl cyclase - cAMP - PKA pathway. IGF-1 autocrine signalling inhibition partially suppressed mitogenic effects revealed by both domain types...
March 2017: Biochemistry and Biophysics Reports
Ting Li, Nannan Liu
This study explores the role of G-protein-coupled receptor-intracellular signaling in the development of P450-mediated insecticide resistance in mosquitoes, Culex quinquefasciatus, focusing on the essential function of the GPCRs and their downstream effectors of Gs alpha subunit protein (Gαs) and adenylyl cyclase (ACs) in P450-mediated insecticide resistance of Culex mosquitoes. Our RNAi-mediated functional study showed that knockdown of Gαs caused the decreased expression of the downstream effectors of ACs and PKAs in the GPCR signaling pathway and resistance P450 genes, whereas knockdown of ACs decreased the expression of PKAs and resistance P450 genes...
December 2017: Biochemistry and Biophysics Reports
Emily Qualls-Creekmore, Ratna Gupta, Masami Yoshimura
The cyclic AMP (cAMP) signaling pathway is implicated in the development of alcohol use disorder. Previous studies have demonstrated that ethanol enhances the activity of adenylyl cyclase (AC) in an isoform specific manner; AC7 is most enhanced by ethanol, and regions responsible for enhancement by ethanol are located in the cytoplasmic domains of the AC7 protein. We hypothesize that ethanol modulates AC activity by directly interacting with the protein and that ethanol effects on AC can be studied using recombinant AC in vitro...
July 2017: Biochemistry and Biophysics Reports
Mari Sepp, Hanna Vihma, Kaja Nurm, Mari Urb, Stephanie Cerceo Page, Kaisa Roots, Anu Hark, Brady J Maher, Priit Pruunsild, Tõnis Timmusk
Transcription factor 4 (TCF4 alias ITF2, E2-2) is a basic helix-loop-helix (bHLH) protein associated with Pitt-Hopkins syndrome, intellectual disability and schizophrenia. Here we show that TCF4-dependent transcription in cortical neurons, cultured from embryonic rats of both sexes, is induced by neuronal activity via soluble adenylyl cyclase and protein kinase A (PKA) signalling. PKA directly phosphorylates TCF4 and a PKA phosphorylation site in TCF4 is necessary for its transcriptional activity in cultured neurons as well as in the developing brain in vivo We also demonstrate that Gadd45g (growth arrest and DNA damage inducible gamma) is a direct target of neuronal activity-induced TCF4-dependent transcriptional regulation and TCF4 missense variations identified in schizophrenia patients alter the transcriptional activity of TCF4 in neurons...
September 26, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jakub Novak, Ondrej Cerny, Adriana Osickova, Irena Linhartova, Jiri Masin, Ladislav Bumba, Peter Sebo, Radim Osicka
Bordetellae, pathogenic to mammals, produce an immunomodulatory adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) that enables them to overcome the innate immune defense of the host. CyaA subverts host phagocytic cells by an orchestrated action of its functional domains, where an extremely catalytically active adenylyl cyclase enzyme is delivered into phagocyte cytosol by a pore-forming repeat-in-toxin (RTX) cytolysin moiety. By targeting sentinel cells expressing the complement receptor 3, known as the CD11b/CD18 (αMβ₂) integrin, CyaA compromises the bactericidal functions of host phagocytes and supports infection of host airways by Bordetellae...
September 24, 2017: Toxins
Meenakshi Tanwar, Lohit Khera, Nemneineng Haokip, Rajeev Kaul, Aruna Naorem, Suneel Kateriya
Cyclic nucleotide signaling pathway plays a significant role in various biological processes such as cell growth, transcription, inflammation, in microbial pathogenesis, etc. Modulation of cyclic nucleotide levels by optogenetic tools has overcome certain limitations of studying transduction cascade by pharmacological agents and has allowed several ways to modulate biological processes in a spatiotemporal manner. Here, we have shown the optogenetic modulation of the cyclooxygenase 2 (Cox-2) gene expression and their downstream effector molecule (PGE2) in HEK-293T cells and the development process of Dictyostelium discoideum via modulating the cyclic nucleotide (cAMP) signaling pathway utilizing photoactivated adenylyl cyclases (PACs) as an optogenetic tool...
September 21, 2017: Scientific Reports
Siri Camee van Keulen, Ursula Rothlisberger
Adenylyl cyclase (AC) is an important messenger involved in G-protein-coupled-receptor signal transduction pathways, which is a well-known target for drug development. AC is regulated by activated stimulatory (Gαs) and inhibitory (Gαi) G proteins in the cytosol. Although experimental studies have shown that these Gα subunits can stimulate or inhibit AC's function in a non-competitive way, it is not well understood what the difference is in their mode of action as both Gα subunits appear structurally very similar in a non-lipidated state...
September 2017: PLoS Computational Biology
John J Guers, Jie Zhang, Sara C Campbell, Marko Oydanich, Dorothy E Vatner, Stephen F Vatner
Exercise training is key to healthful longevity. Since exercise training compliance is difficult, it would be useful to have a therapeutic substitute that mimicked exercise training. We compared the effects of exercise training in wild-type (WT) littermates with adenylyl cyclase type 5 knock out (AC5 KO) mice, a model of enhanced exercise performance. Exercise performance, measured by maximal distance and work to exhaustion, was increased in exercise-trained WT to levels already attained in untrained AC5 KO...
September 8, 2017: Basic Research in Cardiology
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