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  1 / 20829 MEDLINE  
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[PMID]:29283227
[Au] Autor:Kolesnikov SS; Bystrova MF
[Ti] Título:Cyclic AMP: Second Messenger as the First Messenger.
[So] Source:Usp Fiziol Nauk;47(3):3-16, 2016 Jul-Sep.
[Is] ISSN:0301-1798
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Cell-to-cell communications and autocrine/paracrine regulations are mediated by an extracellular signaling network involving secretion of a variety of different factors, hormones, neurotransmitters, and other signaling molecules that are recognized in an extracellular medium by multiple molecular receptors operating in the plasma membrane of cells. Most of plasma membrane receptors belong to the superfamily of heptahelical receptors, many of which are coupled by G-proteins to adenylate cyclase responsible for cAMP production in the cell cytoplasm. The canonical role of cAMP in cell physiology is to serve as a second messenger and universal regulator of intracellular processes. Meanwhile, increasing body of evidence leaves little doubts that stimulated cells can release cAMP into intercellular space, where it may serve as signaling molecule in cell-to-cell communications and autocrine regulations. This review considers the basic concept on mechanisms of intracellular and extracellular signaling with cAMP as the second and first messenger.
[Mh] Termos MeSH primário: Adenilil Ciclases/metabolismo
AMP Cíclico/metabolismo
Células Eucarióticas/metabolismo
Receptores de Superfície Celular/metabolismo
Sistemas do Segundo Mensageiro/genética
[Mh] Termos MeSH secundário: Adenilil Ciclases/genética
Animais
Comunicação Celular
Membrana Celular/metabolismo
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/metabolismo
Células Eucarióticas/citologia
Espaço Extracelular/metabolismo
Regulação da Expressão Gênica
Hormônios/genética
Hormônios/metabolismo
Seres Humanos
Neurotransmissores/genética
Neurotransmissores/metabolismo
Receptores de Superfície Celular/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Hormones); 0 (Neurotransmitter Agents); 0 (Receptors, Cell Surface); E0399OZS9N (Cyclic AMP); EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 6); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171229
[St] Status:MEDLINE


  2 / 20829 MEDLINE  
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[PMID]:29236776
[Au] Autor:Ge L; Gu H; Huang B; Song Q; Stanley D; Liu F; Yang GQ; Wu JC
[Ad] Endereço:School of Horticulture and Plant Protection, Yangzhou University, Yangzhou P.R. China.
[Ti] Título:An adenylyl cyclase like-9 gene (NlAC9) influences growth and fecundity in the brown planthopper, Nilaparvata lugens (Stål) (Hemiptera: Delphacidae).
[So] Source:PLoS One;12(12):e0189214, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cAMP/PKA intracellular signaling pathway is launched by adenylyl cyclase (AC) conversion of adenosine triphosphate (ATP) to 3', 5'-cyclic AMP (cAMP) and cAMP-dependent activation of PKA. Although this pathway is very well known in insect physiology, there is little to no information on it in some very small pest insects, such as the brown planthopper (BPH), Nilaparvata lugens Stål. BPH is a destructive pest responsible for tremendous crop losses in rice cropping systems. We are investigating the potentials of novel pest management technologies from RNA interference perspective. Based on analysis of transcriptomic data, the BPH AC like-9 gene (NlAC9) was up-regulated in post-mating females, which led us to pose the hypothesis that NlAC9 is a target gene that would lead to reduced BPH fitness and populations. Targeting NlAC9 led to substantially decreased soluble ovarian protein content, yeast-like symbiont abundance, and vitellogenin gene expression, accompanied with stunted ovarian development and body size. Eggs laid were decreased and oviposition period shortened. Taken together, our findings indicated that NlAC9 exerted pronounced effects on female fecundity, growth and longevity, which strongly supports our hypothesis.
[Mh] Termos MeSH primário: Adenilil Ciclases/genética
Fertilidade
Hemípteros/fisiologia
[Mh] Termos MeSH secundário: Animais
Hemípteros/enzimologia
Hemípteros/genética
Hemípteros/crescimento & desenvolvimento
Interferência de RNA
RNA Mensageiro/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Messenger); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0189214


  3 / 20829 MEDLINE  
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[PMID]:28747357
[Au] Autor:Yanda MK; Liu Q; Cebotaru L
[Ad] Endereço:Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
[Ti] Título:An inhibitor of histone deacetylase 6 activity, ACY-1215, reduces cAMP and cyst growth in polycystic kidney disease.
[So] Source:Am J Physiol Renal Physiol;313(4):F997-F1004, 2017 Oct 01.
[Is] ISSN:1522-1466
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Adult-onset autosomal-dominant polycystic kidney disease (ADPKD) is caused by mutations in either the or gene, leading to malfunction of their gene products, polycystin 1 or 2. Histone deacetylase 6 (HDAC6) expression and activity are increased in mutant renal epithelial cells. Here we studied the effect of ACY-1215, a specific HDAC6 inhibitor, on cyst growth in ADPKD. Treatment with ACY-1215 slowed cyst growth in a mouse model of ADPKD that forms massive cysts within 3 wk after knockout of polycystin 1 function. It also prevented cyst formation in MDCK.2 cells, an in vitro model of cystogenesis, and in an ADPKD cell line derived from the proximal tubules from a mouse (PN cells). In PN cells ACY-1215 also reduced the size of already established cysts. We found that ACY-1215 lowered cAMP levels and protein expression of adenylyl cyclase 6. Our results suggest that HDAC6 could potentially serve as a therapeutic target in ADPKD.
[Mh] Termos MeSH primário: Inibidores de Histona Desacetilases/uso terapêutico
Ácidos Hidroxâmicos/uso terapêutico
Rim Policístico Autossômico Dominante/tratamento farmacológico
Pirimidinas/uso terapêutico
[Mh] Termos MeSH secundário: Adenilil Ciclases/metabolismo
Animais
AMP Cíclico/metabolismo
Avaliação Pré-Clínica de Medicamentos
Feminino
Desacetilase 6 de Histona
Inibidores de Histona Desacetilases/farmacologia
Histona Desacetilases/metabolismo
Ácidos Hidroxâmicos/farmacologia
Masculino
Camundongos Endogâmicos C57BL
Pirimidinas/farmacologia
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide); 0 (Histone Deacetylase Inhibitors); 0 (Hydroxamic Acids); 0 (Pyrimidines); 0 (Tubulin); E0399OZS9N (Cyclic AMP); EC 3.5.1.98 (Hdac6 protein, mouse); EC 3.5.1.98 (Histone Deacetylase 6); EC 3.5.1.98 (Histone Deacetylases); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171212
[Lr] Data última revisão:
171212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1152/ajprenal.00186.2017


  4 / 20829 MEDLINE  
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[PMID]:28464471
[Au] Autor:Johnson RM; Bai G; DeMott CM; Banavali NK; Montague CR; Moon C; Shekhtman A; VanderVen B; McDonough KA
[Ad] Endereço:Department of Biomedical Sciences, School of Public Health, University at Albany, SUNY, Albany, NY, USA.
[Ti] Título:Chemical activation of adenylyl cyclase Rv1625c inhibits growth of Mycobacterium tuberculosis on cholesterol and modulates intramacrophage signaling.
[So] Source:Mol Microbiol;105(2):294-308, 2017 Jul.
[Is] ISSN:1365-2958
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mycobacterium tuberculosis (Mtb) uses a complex 3', 5'-cyclic AMP (cAMP) signaling network to sense and respond to changing environments encountered during infection, so perturbation of cAMP signaling might be leveraged to disrupt Mtb pathogenesis. However, understanding of cAMP signaling pathways is hindered by the presence of at least 15 distinct adenylyl cyclases (ACs). Recently, the small molecule V-58 was shown to inhibit Mtb replication within macrophages and stimulate cAMP production in Mtb. Here we determined that V-58 rapidly and directly activates Mtb AC Rv1625c to produce high levels of cAMP regardless of the bacterial environment or growth medium. Metabolic inhibition by V-58 was carbon source dependent in Mtb and did not occur in Mycobacterium smegmatis, suggesting that V-58-mediated growth inhibition is due to interference with specific Mtb metabolic pathways rather than a generalized cAMP toxicity. Chemical stimulation of cAMP production by Mtb within macrophages also caused down regulation of TNF-α production by the macrophages, indicating a complex role for cAMP in Mtb pathogenesis. Together these studies describe a novel approach for targeted stimulation of cAMP production in Mtb, and provide new insights into the myriad roles of cAMP signaling in Mtb, particularly during Mtb's interactions with macrophages.
[Mh] Termos MeSH primário: Adenilil Ciclases/genética
Adenilil Ciclases/metabolismo
Mycobacterium tuberculosis/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Bactérias/metabolismo
Colesterol/metabolismo
AMP Cíclico/metabolismo
Regulação Bacteriana da Expressão Gênica/genética
Macrófagos/microbiologia
Mycobacterium smegmatis/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 97C5T2UQ7J (Cholesterol); E0399OZS9N (Cyclic AMP); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1111/mmi.13701


  5 / 20829 MEDLINE  
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[PMID]:28985495
[Au] Autor:Richardson TG; Zheng J; Davey Smith G; Timpson NJ; Gaunt TR; Relton CL; Hemani G
[Ad] Endereço:MRC Integrative Epidemiology Unit, Bristol Medical School (Population Health Sciences), University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK. Electronic address: tom.g.richardson@bristol.ac.uk.
[Ti] Título:Mendelian Randomization Analysis Identifies CpG Sites as Putative Mediators for Genetic Influences on Cardiovascular Disease Risk.
[So] Source:Am J Hum Genet;101(4):590-602, 2017 Oct 05.
[Is] ISSN:1537-6605
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The extent to which genetic influences on cardiovascular disease risk are mediated by changes in DNA methylation levels has not been systematically explored. We developed an analytical framework that integrates genetic fine mapping and Mendelian randomization with epigenome-wide association studies to evaluate the causal relationships between methylation levels and 14 cardiovascular disease traits. We identified ten genetic loci known to influence proximal DNA methylation which were also associated with cardiovascular traits after multiple-testing correction. Bivariate fine mapping provided evidence that the individual variants responsible for the observed effects on cardiovascular traits at the ADCY3 and ADIPOQ loci were potentially mediated through changes in DNA methylation, although we highlight that we are unable to reliably separate causality from horizontal pleiotropy. Estimates of causal effects were replicated with results from large-scale consortia. Genetic variants and CpG sites identified in this study were enriched for histone mark peaks in relevant tissue types and gene promoter regions. Integrating our results with expression quantitative trait loci data, we provide evidence that variation at these regulatory regions is likely to also influence gene expression levels at these loci.
[Mh] Termos MeSH primário: Doenças Cardiovasculares/genética
Ilhas de CpG
Metilação de DNA
Análise da Randomização Mendeliana/métodos
Polimorfismo de Nucleotídeo Único
Locos de Características Quantitativas
[Mh] Termos MeSH secundário: Adenilil Ciclases/genética
Adiponectina/genética
Doenças Cardiovasculares/epidemiologia
Doenças Cardiovasculares/patologia
Criança
Estudos de Coortes
Feminino
Regulação da Expressão Gênica
Genoma Humano
Estudo de Associação Genômica Ampla/métodos
Seres Humanos
Fenótipo
Gravidez
Fatores de Risco
Reino Unido/epidemiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ADIPOQ protein, human); 0 (Adiponectin); EC 4.6.1.1 (Adenylyl Cyclases); EC 4.6.1.1 (adenylate cyclase 3)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171018
[Lr] Data última revisão:
171018
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


  6 / 20829 MEDLINE  
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[PMID]:28945820
[Au] Autor:Guichard A; Jain P; Moayeri M; Schwartz R; Chin S; Zhu L; Cruz-Moreno B; Liu JZ; Aguilar B; Hollands A; Leppla SH; Nizet V; Bier E
[Ad] Endereço:Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA, United States of America.
[Ti] Título:Anthrax edema toxin disrupts distinct steps in Rab11-dependent junctional transport.
[So] Source:PLoS Pathog;13(9):e1006603, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. Both of the primary cAMP effector pathways -PKA and Epac/Rap1- contribute to inhibition of Rab11-mediated trafficking, but act at distinct steps of the delivery process. PKA acts early, preventing Rab11 from associating with its effectors Rip11 and Sec15. In contrast, Epac functions subsequently via the small GTPase Rap1 to block fusion of recycling endosomes with the plasma membrane, and appears to be the primary effector of EF toxicity in this process. Similarly, experiments conducted in mammalian systems reveal that Epac, but not PKA, mediates the activity of EF both in cell culture and in vivo. The small GTPase Arf6, which initiates endocytic retrieval of cell adhesion components, also contributes to junctional homeostasis by counteracting Rab11-dependent delivery of cargo proteins at sites of cell-cell contact. These studies have potentially significant practical implications, since chemical inhibition of either Arf6 or Epac blocks the effect of EF in cell culture and in vivo, opening new potential therapeutic avenues for treating symptoms caused by cAMP-inducing toxins or related barrier-disrupting pathologies.
[Mh] Termos MeSH primário: Antígenos de Bactérias/farmacologia
Toxinas Bacterianas/farmacologia
Edema/metabolismo
Endossomos/efeitos dos fármacos
Junções Intercelulares/efeitos dos fármacos
[Mh] Termos MeSH secundário: Fatores de Ribosilação do ADP/metabolismo
Adenilil Ciclases/metabolismo
Animais
Caderinas/metabolismo
Linhagem Celular
Endossomos/metabolismo
Junções Intercelulares/metabolismo
Transporte Proteico/efeitos dos fármacos
Proteínas rab de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Bacterial); 0 (Bacterial Toxins); 0 (Cadherins); 0 (anthrax toxin); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ADP-ribosylation factor 6); EC 3.6.5.2 (rab GTP-Binding Proteins); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006603


  7 / 20829 MEDLINE  
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Rizzo, Luiz Vicente
Texto completo
[PMID]:28939444
[Au] Autor:Carvalho de Freitas R; Lonien SCH; Malvezi AD; Silveira GF; Wowk PF; da Silva RV; Yamauchi LM; Yamada-Ogatta SF; Rizzo LV; Bordignon J; Pinge-Filho P
[Ad] Endereço:Laboratório de Imunopatologia Experimental, Departamento de Ciências Patológicas, Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86051-970, Londrina, Paraná, Brazil.
[Ti] Título:Trypanosoma cruzi: Inhibition of infection of human monocytes by aspirin.
[So] Source:Exp Parasitol;182:26-33, 2017 Nov.
[Is] ISSN:1090-2449
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell invasion by Trypanosoma cruzi and its intracellular replication are essential for progression of the parasite life cycle and development of Chagas disease. Prostaglandin E2 (PGE ) and other eicosanoids potently modulate host response and contribute to Chagas disease progression. In this study, we evaluated the effect of aspirin (ASA), a non-selective cyclooxygenase (COX) inhibitor on the T. cruzi invasion and its influence on nitric oxide and cytokine production in human monocytes. The pretreatment of monocytes with ASA or SQ 22536 (adenylate-cyclase inhibitor) induced a marked inhibition of T. cruzi infection. On the other hand, the treatment of monocytes with SQ 22536 after ASA restored the invasiveness of T. cruzi. This reestablishment was associated with a decrease in nitric oxide and PGE production, and also an increase of interleukin-10 and interleukin-12 by cells pre-treated with ASA. Altogether, these results reinforce the idea that the cyclooxygenase pathway plays a fundamental role in the process of parasite invasion in an in vitro model of T. cruzi infection.
[Mh] Termos MeSH primário: Adenilil Ciclases/metabolismo
Aspirina/farmacologia
Inibidores de Ciclo-Oxigenase/farmacologia
Monócitos/parasitologia
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adenina/análogos & derivados
Adenina/química
Adenina/farmacologia
Inibidores de Adenilil Ciclase/química
Inibidores de Adenilil Ciclase/farmacologia
Adulto
Animais
Linhagem Celular
Sobrevivência Celular
AMP Cíclico/metabolismo
Citocinas/metabolismo
Dinoprostona/metabolismo
Células Epiteliais/citologia
Células Epiteliais/parasitologia
Seres Humanos
Rim/citologia
Rim/parasitologia
Macaca mulatta
Monócitos/efeitos dos fármacos
Monócitos/metabolismo
Óxido Nítrico/metabolismo
Trypanosoma cruzi/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adenylyl Cyclase Inhibitors); 0 (Cyclooxygenase Inhibitors); 0 (Cytokines); 17318-31-9 (9-(tetrahydro-2-furyl)-adenine); 31C4KY9ESH (Nitric Oxide); E0399OZS9N (Cyclic AMP); EC 4.6.1.1 (Adenylyl Cyclases); JAC85A2161 (Adenine); K7Q1JQR04M (Dinoprostone); R16CO5Y76E (Aspirin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170924
[St] Status:MEDLINE


  8 / 20829 MEDLINE  
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[PMID]:28934339
[Au] Autor:Rudkin JK; McLoughlin RM; Preston A; Massey RC
[Ad] Endereço:School of Microbiology, University College Cork, Cork, Ireland.
[Ti] Título:Bacterial toxins: Offensive, defensive, or something else altogether?
[So] Source:PLoS Pathog;13(9):e1006452, 2017 Sep.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The secretion of proteins that damage host tissue is well established as integral to the infectious processes of many bacterial pathogens. However, recent advances in our understanding of the activity of toxins suggest that the attributes we have assigned to them from early in vitro experimentation have misled us into thinking of them as merely destructive tools. Here, we will discuss the multifarious ways in which toxins contribute to the lifestyle of bacteria and, by considering their activity from an evolutionary perspective, demonstrate how this extends far beyond their ability to destroy host tissue.
[Mh] Termos MeSH primário: Adenilil Ciclases/metabolismo
Bactérias/metabolismo
Toxinas Bacterianas/metabolismo
Evolução Biológica
Interações Hospedeiro-Patógeno/imunologia
[Mh] Termos MeSH secundário: Animais
Toxinas Bacterianas/imunologia
Toxinas Bacterianas/toxicidade
Seres Humanos
Superantígenos/imunologia
Superantígenos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bacterial Toxins); 0 (Superantigens); EC 4.6.1.1 (Adenylyl Cyclases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006452


  9 / 20829 MEDLINE  
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[PMID]:28892485
[Au] Autor:van Keulen SC; Rothlisberger U
[Ad] Endereço:Institut des Sciences et Ingénierie Chimiques, École Polytechnicque Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
[Ti] Título:Exploring the inhibition mechanism of adenylyl cyclase type 5 by n-terminal myristoylated Gαi1.
[So] Source:PLoS Comput Biol;13(9):e1005673, 2017 Sep.
[Is] ISSN:1553-7358
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. However, a significant difference between Gαs and Gαi is that while Gαs does not require any lipidation in order to stimulate AC, N-terminal myristoylation is crucial for Gαi's inhibitory function as AC is not inhibited by non-myristoylated Gαi. At present, only the conformation of the complex including Gαs and AC has been resolved via X-ray crystallography. Therefore, understanding the interaction between Gαi and AC is important as it will provide more insight into the unknown mechanism of AC regulation. This study demonstrates via classical molecular dynamics simulations that the myristoylated Gαi1 structure is able to interact with apo adenylyl cyclase type 5 in a way that causes inhibition of the catalytic function of the enzyme, suggesting that Gα lipidation could play a crucial role in AC regulation and in regulating G protein function by affecting Gαi's active conformation.
[Mh] Termos MeSH primário: Adenilil Ciclases/química
Adenilil Ciclases/metabolismo
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/química
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Seres Humanos
Simulação de Dinâmica Molecular
Ácidos Mirísticos
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Myristic Acids); EC 3.6.5.1 (GTP-Binding Protein alpha Subunits, Gi-Go); EC 4.6.1.1 (Adenylyl Cyclases); EC 4.6.1.1 (adenylyl cyclase type V)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pcbi.1005673


  10 / 20829 MEDLINE  
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[PMID]:28877031
[Au] Autor:Zhang G; Feenstra B; Bacelis J; Liu X; Muglia LM; Juodakis J; Miller DE; Litterman N; Jiang PP; Russell L; Hinds DA; Hu Y; Weirauch MT; Chen X; Chavan AR; Wagner GP; Pavlicev M; Nnamani MC; Maziarz J; Karjalainen MK; Rämet M; Sengpiel V; Geller F; Boyd HA; Palotie A; Momany A; Bedell B; Ryckman KK; Huusko JM; Forney CR; Kottyan LC; Hallman M; Teramo K; Nohr EA; Davey Smith G; Melbye M; Jacobsson B; Muglia LJ
[Ad] Endereço:From the Division of Human Genetics (G.Z., L.J.M.), Center for Autoimmune Genomics and Etiology (M.T.W., D.E.M., X.C., C.R.F., L.C.K.) and the Divisions of Biomedical Informatics and Developmental Biology (M.T.W.), Cincinnati Children's Hospital Medical Center, and the Center for Prevention of Prete
[Ti] Título:Genetic Associations with Gestational Duration and Spontaneous Preterm Birth.
[So] Source:N Engl J Med;377(12):1156-1167, 2017 09 21.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Despite evidence that genetic factors contribute to the duration of gestation and the risk of preterm birth, robust associations with genetic variants have not been identified. We used large data sets that included the gestational duration to determine possible genetic associations. METHODS: We performed a genomewide association study in a discovery set of samples obtained from 43,568 women of European ancestry using gestational duration as a continuous trait and term or preterm (<37 weeks) birth as a dichotomous outcome. We used samples from three Nordic data sets (involving a total of 8643 women) to test for replication of genomic loci that had significant genomewide association (P<5.0×10 ) or an association with suggestive significance (P<1.0×10 ) in the discovery set. RESULTS: In the discovery and replication data sets, four loci (EBF1, EEFSEC, AGTR2, and WNT4) were significantly associated with gestational duration. Functional analysis showed that an implicated variant in WNT4 alters the binding of the estrogen receptor. The association between variants in ADCY5 and RAP2C and gestational duration had suggestive significance in the discovery set and significant evidence of association in the replication sets; these variants also showed genomewide significance in a joint analysis. Common variants in EBF1, EEFSEC, and AGTR2 showed association with preterm birth with genomewide significance. An analysis of mother-infant dyads suggested that these variants act at the level of the maternal genome. CONCLUSIONS: In this genomewide association study, we found that variants at the EBF1, EEFSEC, AGTR2, WNT4, ADCY5, and RAP2C loci were associated with gestational duration and variants at the EBF1, EEFSEC, and AGTR2 loci with preterm birth. Previously established roles of these genes in uterine development, maternal nutrition, and vascular control support their mechanistic involvement. (Funded by the March of Dimes and others.).
[Mh] Termos MeSH primário: Predisposição Genética para Doença
Variação Genética
Idade Gestacional
Fatores de Alongamento de Peptídeos/genética
Nascimento Prematuro/genética
Receptor Tipo 2 de Angiotensina/genética
Transativadores/genética
[Mh] Termos MeSH secundário: Adenilil Ciclases/genética
Conjuntos de Dados como Assunto
Feminino
Estudo de Associação Genômica Ampla
Seres Humanos
Fenótipo
Polimorfismo de Nucleotídeo Único
Gravidez
Análise de Regressão
Proteína Wnt4/genética
Proteínas ras/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (EBF1 protein, human); 0 (EEFSEC protein, human); 0 (Peptide Elongation Factors); 0 (Receptor, Angiotensin, Type 2); 0 (Trans-Activators); 0 (Wnt4 Protein); EC 3.6.1.- (Rap2C protein, human); EC 3.6.5.2 (ras Proteins); EC 4.6.1.1 (Adenylyl Cyclases); EC 4.6.1.1 (adenylyl cyclase type V)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170907
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1612665



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