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Adenylyl cyclases

Ladislav Bumba, Jiri Masin, Adriana Osickova, Radim Osicka, Peter Sebo
The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) plays a crucial role in virulence and airway colonization capacity of the whooping cough agent Bordetella pertussis . The toxin penetrates target cell membranes and exhibits three distinct biological activities. A population of CyaA conformers forms small cation-selective pores that permeabilize the cell membrane for potassium efflux, which can provoke colloid-osmotic (oncotic) cell lysis. The other two activities are due to CyaA conformers that transiently form calcium influx conduits in the target cell membrane and translocate the adenylate cyclase (AC) enzyme into cytosol of cells...
June 16, 2018: Toxins
Martin Tresguerres, Cristina Salmerón
The enzyme soluble adenylyl cyclase (sAC) is the most recently identified source of the messenger molecule cyclic adenosine monophosphate. sAC is evolutionarily conserved from cyanobacteria to human, is directly stimulated by [Formula: see text] ions, and can act as a sensor of environmental and metabolic CO2 , pH, and [Formula: see text] levels. sAC genes tend to have multiple alternative promoters, undergo extensive alternative splicing, be translated into low mRNA levels, and the numerous sAC protein isoforms may be present in various subcellular localizations...
2018: Methods in Enzymology
Lirit N Franks, Benjamin M Ford, Toshifumi Fujiwara, Haibo Zhao, Paul L Prather
Selective estrogen receptor modulators (SERMs) target estrogen receptors (ERs) to treat breast cancer and osteoporosis. Several SERMs exhibit anti-cancer activity not related to ERs. To discover novel anti-cancer drugs acting via ER-independent mechanisms, derivatives of the SERM tamoxifen, known as the "ridaifen" compounds, have been developed that exhibit reduced or no ER affinity, while maintaining cytotoxicity. Tamoxifen and other SERMs bind to cannabinoid receptors with moderate affinity. Therefore, ER-independent effects of SERMs might be mediated via cannabinoid receptors...
June 12, 2018: Toxicology and Applied Pharmacology
Antoine Koehl, Hongli Hu, Shoji Maeda, Yan Zhang, Qianhui Qu, Joseph M Paggi, Naomi R Latorraca, Daniel Hilger, Roger Dawson, Hugues Matile, Gebhard F X Schertler, Sebastien Granier, William I Weis, Ron O Dror, Aashish Manglik, Georgios Skiniotis, Brian K Kobilka
The μ-opioid receptor (μOR) is a G-protein-coupled receptor (GPCR) and the target of most clinically and recreationally used opioids. The induced positive effects of analgesia and euphoria are mediated by μOR signalling through the adenylyl cyclase-inhibiting heterotrimeric G protein Gi . Here we present the 3.5 Å resolution cryo-electron microscopy structure of the μOR bound to the agonist peptide DAMGO and nucleotide-free Gi . DAMGO occupies the morphinan ligand pocket, with its N terminus interacting with conserved receptor residues and its C terminus engaging regions important for opioid-ligand selectivity...
June 13, 2018: Nature
Nathan H Wray, Jeffrey M Schappi, Harinder Singh, Nicolas B Senese, Mark M Rasenick
Ketamine produces rapid and robust antidepressant effects in depressed patients within hours of administration, often when traditional antidepressant compounds have failed to alleviate symptoms. We hypothesized that ketamine would translocate Gαs from lipid rafts to non-raft microdomains, similarly to other antidepressants but with a distinct, abbreviated treatment duration. C6 glioma cells were treated with 10 µM ketamine for 15 min, which translocated Gαs from lipid raft domains to non-raft domains...
June 12, 2018: Molecular Psychiatry
Yvonne Koch, Pauline Wimberger, Ruth Grümmer
Endometriosis, characterized by the presence of endometrial tissue at ectopic sites, is a leading cause of pelvic pain and subfertility in women. The stromal compartment of the endometrium is considered to play a pivotal role in the establishment and persistence of endometriotic lesions, thus impaired decidualization of these cells may result in enhanced invasion capacity at ectopic sites. Consequently, stimulation of decidualization may alleviate this disease. To analyze the effect of systemically applied compounds on decidualization of ectopic endometrial tissue, endometriosis was induced by suturing human eutopic endometrium to the peritoneum of 22 NOD/SCID mice...
January 1, 2018: Experimental Biology and Medicine
Paul W Kriebel, Ritankar Majumdar, Lisa M Jenkins, Hiroshi Senoo, Weiye Wang, Sonia Ammu, Song Chen, Kedar Narayan, Miho Iijima, Carole A Parent
Chemotactic signals are relayed to neighboring cells through the secretion of additional chemoattractants. We previously showed in Dictyostelium discoideum that the adenylyl cyclase A, which synthesizes the chemoattractant cyclic adenosine monophosphate (cAMP), is present in the intraluminal vesicles of multivesicular bodies (MVBs) that coalesce at the back of cells. Using ultrastructural reconstructions, we now show that ACA-containing MVBs release their contents to attract neighboring cells. We show that the released vesicles are capable of directing migration and streaming and are central to chemotactic signal relay...
June 8, 2018: Journal of Cell Biology
András Spät, Gergő Szanda
The biological effects of physiological stimuli of adrenocortical glomerulosa cells are predominantly mediated by the Ca2+ and the cAMP signal transduction pathways. The complex interplay between these signalling systems fine-tunes aldosterone secretion. In addition to the well-known cytosolic interactions, a novel intramitochondrial Ca2+ -cAMP interplay has been recently recognised. The cytosolic Ca2+ signal is rapidly transferred into the mitochondrial matrix where it activates Ca2+ -sensitive dehydrogenases, thus enhancing the formation of NADPH, a cofactor of steroid synthesis...
June 6, 2018: Pflügers Archiv: European Journal of Physiology
Murali Yanda, Qiangni Liu, Liudmila Cebotaru
Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive enlargement of cysts, leading to a decline in function and renal failure that cannot be prevented by current treatments. Mutations in pkd1 and pkd2, encoding the polycystin 1 and 2 proteins, induce growth-related pathways, including heat shock proteins, as occurs in some cancers raising the prospect that pharmacological interventions that target these pathways might alleviate or prevent ADPKD. Here, we demonstrate a role for VX-809, a corrector of cystic fibrosis transmembrane conductance regulator (CFTR) conventionally used to manage cystic fibrosis, in reducing renal cyst growth...
June 6, 2018: Journal of Biological Chemistry
Christopher M Gonçalves, Daniel K Mulkey
KEY POINTS: changes in CO2 result in corresponding changes in both H+ and HCO3 - and despite evidence that HCO3 - can function as an independent signaling molecule, there is little evidence suggesting HCO3 - contributes to respiratory chemoreception. We show that HCO3 - directly activates chemosensitive RTN neurons. Identifying all relevant signaling molecules is essential for understanding how chemoreceptors function, and since HCO3 - and H+ are buffered by separate cellular mechanisms, having the ability to sense both modalities adds additional information regarding changes in CO2 that are not necessarily reflected by pH alone...
June 5, 2018: Journal of Physiology
Rachelle W Johnson, Yao Sun, Patricia W M Ho, Audrey S M Chan, Jasmine A Johnson, Nathan J Pavlos, Natalie A Sims, T John Martin
Parathyroid hormone-related protein (PTHrP) expression in breast cancer is enriched in bone metastases compared to primary tumors. Human MCF7 breast cancer cells "home" to the bones of immune deficient mice following intracardiac inoculation, but do not grow well and stain negatively for Ki67, thus serving as a model of breast cancer dormancy in vivo . We have previously shown that PTHrP overexpression in MCF7 cells overcomes this dormant phenotype, causing them to grow as osteolytic deposits, and that PTHrP-overexpressing MCF7 cells showed significantly lower expression of genes associated with dormancy compared to vector controls...
2018: Frontiers in Endocrinology
Lea Weber, Wolfgang A Schulz, Stathis Philippou, Josephine Eckardt, Burkhard Ubrig, Michéle J Hoffmann, Andrea Tannapfel, Benjamin Kalbe, Günter Gisselmann, Hanns Hatt
Olfactory receptors (ORs) are a large group of G-protein coupled receptors predominantly found in the olfactory epithelium. Many ORs are, however, ectopically expressed in other tissues and involved in several diseases including cancer. In this study, we describe that one OR, OR10H1, is predominantly expressed in the human urinary bladder with a notably higher expression at mRNA and protein level in bladder cancer tissues. Interestingly, also significantly higher amounts of OR10H1 transcripts were detectable in the urine of bladder cancer patients than in the urine of control persons...
2018: Frontiers in Physiology
Gabrielle M Pine, Hashini M Batugedara, Meera G Nair
The Resistin-Like Molecules (RELM) α, β, and γ and their namesake, resistin, share structural and sequence homology but exhibit significant diversity in expression and function within their mammalian host. RELM proteins are expressed in a wide range of diseases, such as: microbial infections (eg. bacterial and helminth), inflammatory diseases (eg. asthma, fibrosis) and metabolic disorders (eg. diabetes). While the expression pattern and molecular regulation of RELM proteins are well characterized, much controversy remains over their proposed functions, with evidence of host-protective and pathogenic roles...
June 1, 2018: Cytokine
K V Derkach, I B Sukhov, V M Bondareva, A O Shpakov
Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in the recent years to treat obesity. Its therapeutic effect is due not only to the influence on the peripheral tissues, but also on the hypothalamus, which controls food behavior and energy metabolism. The aim was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate/high-fat diet on the metabolic and hormonal parameters and functional state of the hypothalamic signaling systems...
2018: Advances in Gerontology, Uspekhi Gerontologii
Shakarr V Wiggins, Clemens Steegborn, Lonny R Levin, Jochen Buck
Cyclic AMP (cAMP), the prototypical second messenger, has been implicated in a wide variety of (often opposing) physiological processes. It simultaneously mediates multiple, diverse processes, often within a single cell, by acting locally within independently-regulated and spatially-restricted microdomains. Within each microdomain, the level of cAMP will be dependent upon the balance between its synthesis by adenylyl cyclases and its degradation by phosphodiesterases (PDEs). In mammalian cells, there are many PDE isoforms and two types of adenylyl cyclases; the G protein regulated transmembrane adenylyl cyclases (tmACs) and the CO2 /HCO3 - /pH-, calcium-, and ATP- sensing soluble adenylyl cyclase (sAC)...
May 25, 2018: Pharmacology & Therapeutics
Jie Zhang, Daniel Levy, Marko Oydanich, Claudio A Bravo, Seonghun Yoon, Dorothy E Vatner, Stephen F Vatner
We developed a novel adenylyl cyclase type 5 (AC5) inhibitor, C90, that reduces myocardial infarct size even when administered after coronary reperfusion. This is key, since it is not practical to administer a drug to a patient with myocardial infarction before revascularization, and is one reason why so many prior drugs, which reduced infarct in experimental animals, failed in clinical trials. C90 is the most potent AC5 inhibitor, as exhibited by its IC50 value for AC5 inhibition, which was 5 times lower than the next most potent AC5 inhibitor...
May 22, 2018: Journal of Molecular and Cellular Cardiology
Ulrike Scheib, Matthias Broser, Oana M Constantin, Shang Yang, Shiqiang Gao, Shatanik Mukherjee, Katja Stehfest, Georg Nagel, Christine E Gee, Peter Hegemann
The cyclic nucleotides cAMP and cGMP are important second messengers that orchestrate fundamental cellular responses. Here, we present the characterization of the rhodopsin-guanylyl cyclase from Catenaria anguillulae (CaRhGC), which produces cGMP in response to green light with a light to dark activity ratio >1000. After light excitation the putative signaling state forms with τ = 31 ms and decays with τ = 570 ms. Mutations (up to 6) within the nucleotide binding site generate rhodopsin-adenylyl cyclases (CaRhACs) of which the double mutated YFP-CaRhAC (E497K/C566D) is the most suitable for rapid cAMP production in neurons...
May 24, 2018: Nature Communications
David Acton, Matthew J Broadhead, Gareth Brian Miles
Astrocytes modulate many neuronal networks, including spinal networks responsible for the generation of locomotor behaviour. Astrocytic modulation of spinal motor circuits involves release of ATP from astrocytes, hydrolysation of ATP to adenosine, and subsequent activation of neuronal A1 adenosine receptors (A1Rs). The net effect of this pathway is a reduction in the frequency of locomotor-related activity. Recently, it was proposed that A1Rs modulate burst frequency by blocking the D1-like dopamine receptor (D1LR) signalling pathway; however, adenosine also modulates ventral horn circuits by dopamine-independent pathways...
May 23, 2018: Journal of Neurophysiology
Chathura Priyadarshana, Atsushi Tajima, Naoto Ishikawa, Atsushi Asano
Both transcriptionally and translationally inactive sperm need preassembled pathways into specific cellular compartments to function. Although initiation of the acrosome reaction (AR) involves several signaling pathways including protein kinase A (PKA) activation, how these are regulated remains poorly understood in avian sperm. Membrane rafts are specific membrane regions enriched in sterols and functional proteins and play important roles in diverse cellular processes, including signal transduction. Our recent studies on chicken sperm demonstrated that membrane rafts exist and play a role in multistage fertilization...
May 18, 2018: Biology of Reproduction
Hui-Rong Xi, Hui-Ping Ma, Fang-Fang Yang, Yu-Hai Gao, Jian Zhou, Yuan-Yuan Wang, Wen-Yuan Li, Cory J Xian, Ke-Ming Chen
ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium sagittatum brevicornum Maxim. is an important traditional Chinese herb that has long been used to promote bone fracture healing and treat osteoporosis. AIM OF THE STUDY: Achieving peak bone mass by adolescence has now been accepted to be fundamental for preventing osteoporosis in adulthood life. This study investigated the possibility of increasing peak bone mass in young rats using the total flavonoid extract of Epimedium herb (TFE)...
May 18, 2018: Journal of Ethnopharmacology
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