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[PMID]:29300939
[Au] Autor:Tian Y; Heng D; Xu K; Liu W; Weng X; Hu X; Zhang C
[Ad] Endereço:College of Life Science, Capital Normal University, Beijing, People's Republic of China.
[Ti] Título:cGMP/PKG-I Pathway-Mediated GLUT1/4 Regulation by NO in Female Rat Granulosa Cells.
[So] Source:Endocrinology;159(2):1147-1158, 2018 02 01.
[Is] ISSN:1945-7170
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nitric oxide (NO) is a multifunctional gaseous molecule that plays important roles in mammalian reproductive functions, including follicular growth and development. Although our previous study showed that NO mediated 3,5,3'-triiodothyronine and follicle-stimulating hormone-induced granulosa cell development via upregulation of glucose transporter protein (GLUT)1 and GLUT4 in granulosa cells, little is known about the precise mechanisms regulating ovarian development via glucose. The objective of the present study was to determine the cellular and molecular mechanism by which NO regulates GLUT expression and glucose uptake in granulosa cells. Our results indicated that NO increased GLUT1/GLUT4 expression and translocation in cells, as well as glucose uptake. These changes were accompanied by upregulation of cyclic guanosine monophosphate (cGMP) level and cGMP-dependent protein kinase (PKG)-I protein content. The results of small interfering RNA (siRNA) analysis showed that knockdown of PKG-I significantly attenuated gene expression, translocation, and glucose uptake. Moreover, the PKG-I inhibitor also blocked the above processes. Furthermore, NO induced cyclic adenosine monophosphate response element binding factor (CREB) phosphorylation, and CREB siRNA attenuated NO-induced GLUT expression, translocation, and glucose uptake in granulosa cells. These findings suggest that NO increases cellular glucose uptake via GLUT upregulation and translocation, which are mediated through the activation of the cGMP/PKG pathway. Meanwhile, the activated CREB is also involved in the regulation. These findings indicate that NO has an important influence on the glucose uptake of granulosa cells.
[Mh] Termos MeSH primário: Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
GMP Cíclico/metabolismo
Transportador de Glucose Tipo 1/genética
Transportador de Glucose Tipo 4/genética
Células da Granulosa/efeitos dos fármacos
Óxido Nítrico/farmacologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Feminino
Regulação da Expressão Gênica/efeitos dos fármacos
Transportador de Glucose Tipo 1/metabolismo
Transportador de Glucose Tipo 4/metabolismo
Células da Granulosa/metabolismo
Ratos
Ratos Sprague-Dawley
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Glucose Transporter Type 1); 0 (Glucose Transporter Type 4); 0 (Slc2a1 protein, rat); 0 (Slc2a4 protein, rat); 31C4KY9ESH (Nitric Oxide); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180215
[Lr] Data última revisão:
180215
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180105
[St] Status:MEDLINE
[do] DOI:10.1210/en.2017-00863


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[PMID]:28743500
[Au] Autor:Manivasagam S; Vellaichamy E
[Ad] Endereço:Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600025, India.
[Ti] Título:Suppression of Npr1, not Npr2 gene function induces hypertrophic growth in H9c2 cells in vitro.
[So] Source:Biochem Biophys Res Commun;491(2):250-256, 2017 09 16.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Npr1 gene (coding for NPR-A) and Npr2 gene (coding for NPR-B) are identified as intrinsic anti-hypertrophic genes that opposes abnormal cardiac remodeling. However, the functional role of Npr1 and Npr2 genes during cardiac hypertrophic growth is not well understood. Hence, the present investigation was aimed to study the effect of Npr1 and Npr2 gene silencing, respectively on ß-AR activation induced cardiac hypertrophic growth in H9c2 cells in vitro. The control, Npr1, and Npr2 gene suppressed H9c2 cells, respectively were treated with ISO (10 M) for 48 h. The mRNA and protein expression profile of NPR-A, NPR-B, PKG-I and cGMP were analyzed by qPCR, Western blotting, ELISA, and immunofluorescence methods, respectively. A marked increase in cell size (30.10 ± 0.51 µm vs 61.83 ± 0.43 µm, 2-fold) accompanied by elevated hypertrophic marker genes (α-sk and ß-MHC 3-fold, respectively) expression was observed in Npr1 gene suppressed H9c2 cells as compared with control cells. In contrast, the Npr2 gene suppression in H9c2 cells neither altered the cell size nor the level of hypertrophic marker genes expression. Upon exposure to Isoproterenol, the Npr1 suppressed H9c2 cells exhibited further increase in cell size (1.5 fold), whereas, no significant increase in cell size or marker genes expression was noticed in Npr2 suppressed cells. Moreover, the intracellular cGMP level was down-regulated by 2-fold in Npr1 suppressed cells, while, no significant change was observed in Npr2 suppressed cells. Together, these results suggest that Npr1, not Npr2 gene function is positively associated with the initiation of cardiac fetal gene program and development of cardiac hypertrophic growth.
[Mh] Termos MeSH primário: Miócitos Cardíacos/metabolismo
Receptores Adrenérgicos beta 1/genética
Receptores do Fator Natriurético Atrial/genética
[Mh] Termos MeSH secundário: Agonistas Adrenérgicos beta/farmacologia
Animais
Linhagem Celular
Proliferação Celular/efeitos dos fármacos
Tamanho Celular/efeitos dos fármacos
GMP Cíclico/metabolismo
Proteína Quinase Dependente de GMP Cíclico Tipo I/genética
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
Regulação da Expressão Gênica
Isoproterenol/farmacologia
Miócitos Cardíacos/efeitos dos fármacos
Miócitos Cardíacos/patologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Ratos
Receptores Adrenérgicos beta 1/metabolismo
Receptores do Fator Natriurético Atrial/antagonistas & inibidores
Receptores do Fator Natriurético Atrial/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adrenergic beta-Agonists); 0 (RNA, Small Interfering); 0 (Receptors, Adrenergic, beta-1); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); EC 4.6.1.2 (Receptors, Atrial Natriuretic Factor); EC 4.6.1.2 (atrial natriuretic factor receptor A); EC 4.6.1.2 (atrial natriuretic factor receptor B); H2D2X058MU (Cyclic GMP); L628TT009W (Isoproterenol)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171129
[Lr] Data última revisão:
171129
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE


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[PMID]:28793191
[Au] Autor:Campbell JC; Henning P; Franz E; Sankaran B; Herberg FW; Kim C
[Ad] Endereço:Structural and Computational Biology and Molecular Biophysics Program, Baylor College of Medicine , Houston, Texas, United States.
[Ti] Título:Structural Basis of Analog Specificity in PKG I and II.
[So] Source:ACS Chem Biol;12(9):2388-2398, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cyclic GMP analogs, 8-Br, 8-pCPT, and PET-cGMP, have been widely used for characterizing cellular functions of cGMP-dependent protein kinase (PKG) I and II isotypes. However, interpreting results obtained using these analogs has been difficult due to their low isotype specificity. Additionally, each isotype has two binding sites with different cGMP affinities and analog selectivities, making understanding the molecular basis for isotype specificity of these compounds even more challenging. To determine isotype specificity of cGMP analogs and their structural basis, we generated the full-length regulatory domains of PKG I and II isotypes with each binding site disabled, determined their affinities for these analogs, and obtained cocrystal structures of both isotypes bound with cGMP analogs. Our affinity and activation measurements show that PET-cGMP is most selective for PKG I, whereas 8-pCPT-cGMP is most selective for PKG II. Our structures of cyclic nucleotide binding (CNB) domains reveal that the B site of PKG I is more open and forms a unique π/π interaction through Arg285 at ß4 with the PET moiety, whereas the A site of PKG II has a larger ß5/ß6 pocket that can better accommodate the bulky 8-pCPT moiety. Our structural and functional results explain the selectivity of these analogs for each PKG isotype and provide a starting point for the rational design of isotype selective activators.
[Mh] Termos MeSH primário: Proteína Quinase Dependente de GMP Cíclico Tipo II/metabolismo
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
GMP Cíclico/análogos & derivados
Tionucleotídeos/metabolismo
[Mh] Termos MeSH secundário: Cristalografia por Raios X
GMP Cíclico/metabolismo
Proteína Quinase Dependente de GMP Cíclico Tipo I/química
Proteína Quinase Dependente de GMP Cíclico Tipo II/química
Seres Humanos
Modelos Moleculares
Conformação Proteica
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Thionucleotides); 54364-02-2 (8-((4-chlorophenyl)thio)cyclic-3',5'-GMP); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type II); H2D2X058MU (Cyclic GMP)
[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:170810
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00369


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[PMID]:28716990
[Au] Autor:Burgoyne JR; Prysyazhna O; Richards DA; Eaton P
[Ad] Endereço:From the Cardiovascular Division, the British Heart Foundation Centre of Excellence, the Rayne Institute, St Thomas' Hospital, King's College London, United Kingdom. joseph.burgoyne@kcl.ac.uk philip.eaton@kcl.ac.uk.
[Ti] Título:Proof of Principle for a Novel Class of Antihypertensives That Target the Oxidative Activation of PKG Iα (Protein Kinase G Iα).
[So] Source:Hypertension;70(3):577-586, 2017 Sep.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Arterial hypertension continues to be a major health burden. Development of new antihypertensive drugs that engage vasodilatory mechanisms not harnessed by available therapies offer therapeutic potential. Oxidants induce an interprotein disulfide in PKG Iα (protein kinase G Iα) at C42, which is associated with its targeting and activation, resulting in vasodilation and blood pressure lowering. Consequently, we developed an assay and screened for electrophilic drugs that activate PKG Iα by selectively targeting C42, as such compounds have potential as novel antihypertensives with a mechanism of action that differs from current therapies. In this way, a drug that we termed G1 was identified, which targets C42 of PKG Iα to induce vasodilation of isolated resistance blood vessels and blood pressure lowering in a mouse model of angiotensin II-induced hypertension. In contrast, these antihypertensive effects were deficient in angiotensin II-induced hypertensive C42S PKG Iα knockin mice. These transgenic mice were engineered to have the reactive cysteinyl thiol replaced with a hydroxyl so that it cannot react with endogenous vasodilatory oxidants or electrophiles such as drug G1. These studies, therefore, provide validation of PKG Iα C42 as the target of G1, as well as proof-of-principle for a new class of antihypertensive drugs that have potential for further development for clinical use in humans.
[Mh] Termos MeSH primário: Anti-Hipertensivos/farmacologia
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
Hipertensão
Músculo Liso Vascular
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Pressão Sanguínea/efeitos dos fármacos
Pressão Sanguínea/fisiologia
Modelos Animais de Doenças
Hipertensão/tratamento farmacológico
Hipertensão/metabolismo
Hipertensão/fisiopatologia
Camundongos
Músculo Liso Vascular/efeitos dos fármacos
Músculo Liso Vascular/metabolismo
Oxirredução/efeitos dos fármacos
Resultado do Tratamento
Vasodilatação/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antihypertensive Agents); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.117.09670


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[PMID]:28360102
[Au] Autor:Kalyanaraman H; Zhuang S; Pilz RB; Casteel DE
[Ad] Endereço:From the Department of Medicine, University of California, San Diego, La Jolla, California 92093.
[Ti] Título:The activity of cGMP-dependent protein kinase Iα is not directly regulated by oxidation-induced disulfide formation at cysteine 43.
[So] Source:J Biol Chem;292(20):8262-8268, 2017 May 19.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The type I cGMP-dependent protein kinases (PKGs) are key regulators of smooth muscle tone, cardiac hypertrophy, and other physiological processes. The two isoforms PKGIα and PKGIß are thought to have unique functions because of their tissue-specific expression, different cGMP affinities, and isoform-specific protein-protein interactions. Recently, a non-canonical pathway of PKGIα activation has been proposed, in which PKGIα is activated in a cGMP-independent fashion via oxidation of Cys , resulting in disulfide formation within the PKGIα N-terminal dimerization domain. A "redox-dead" knock-in mouse containing a C43S mutation exhibits phenotypes consistent with decreased PKGIα signaling, but the detailed mechanism of oxidation-induced PKGIα activation is unknown. Therefore, we examined oxidation-induced activation of PKGIα, and in contrast to previous findings, we observed that disulfide formation at Cys does not directly activate PKGIα or in intact cells. In transfected cells, phosphorylation of Ras homolog gene family member A (RhoA) and vasodilator-stimulated phosphoprotein was increased in response to 8-CPT-cGMP treatment, but not when disulfide formation in PKGIα was induced by H O Using purified enzymes, we found that the Cys oxidation had no effect on basal kinase activity or and values; however, PKGIα containing the C43S mutation was less responsive to cGMP-induced activation. This reduction in cGMP affinity may in part explain the PKGIα loss-of-function phenotype of the C43S knock-in mouse. In conclusion, disulfide formation at Cys does not directly activate PKGIα, and the C43S-mutant PKGIα has a higher for cGMP. Our results highlight that mutant enzymes should be carefully biochemically characterized before making inferences.
[Mh] Termos MeSH primário: Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
Dissulfetos/metabolismo
Multimerização Proteica/fisiologia
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Animais
Linhagem Celular
GMP Cíclico/análogos & derivados
GMP Cíclico/farmacologia
Proteína Quinase Dependente de GMP Cíclico Tipo I/genética
Ativação Enzimática/efeitos dos fármacos
Ativação Enzimática/fisiologia
Técnicas de Introdução de Genes
Seres Humanos
Camundongos
Camundongos Transgênicos
Mutação de Sentido Incorreto
Oxirredução
Multimerização Proteica/efeitos dos fármacos
Tionucleotídeos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disulfides); 0 (Thionucleotides); 54364-02-2 (8-((4-chlorophenyl)thio)cyclic-3',5'-GMP); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170608
[Lr] Data última revisão:
170608
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.C117.787358


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[PMID]:28280239
[Au] Autor:Sharma AK; Birrane G; Anklin C; Rigby AC; Alper SL
[Ad] Endereço:From the Division of Nephrology and Center for Vascular Biology Research, aksharma@bidmc.harvard.edu namasal34@gmail.com.
[Ti] Título:NMR insight into myosin-binding subunit coiled-coil structure reveals binding interface with protein kinase G-Iα leucine zipper in vascular function.
[So] Source:J Biol Chem;292(17):7052-7065, 2017 Apr 28.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nitrovasodilators relax vascular smooth-muscle cells in part by modulating the interaction of the C-terminal coiled-coil domain (CC) and/or the leucine zipper (LZ) domain of the myosin light-chain phosphatase component, myosin-binding subunit (MBS), with the N-terminal LZ domain of protein kinase G (PKG)-Iα. Despite the importance of vasodilation in cardiovascular homeostasis and therapy, our structural understanding of the MBS CC interaction with LZ PKG-1α has remained limited. Here, we report the 3D NMR solution structure of homodimeric CC MBS in which amino acids 932-967 form a coiled-coil of two monomeric α-helices in parallel orientation. We found that the structure is stabilized by non-covalent interactions, with dominant contributions from hydrophobic residues at and heptad positions. Using NMR chemical-shift perturbation (CSP) analysis, we identified a subset of hydrophobic and charged residues of CC MBS (localized within and adjacent to the C-terminal region) contributing to the dimer-dimer interaction interface between homodimeric CC MBS and homodimeric LZ PKG-Iα. N backbone relaxation NMR revealed the dynamic features of the CC MBS interface residues identified by NMR CSP. Paramagnetic relaxation enhancement- and CSP-NMR-guided HADDOCK modeling of the dimer-dimer interface of the heterotetrameric complex exhibits the involvement of non-covalent intermolecular interactions that are localized within and adjacent to the C-terminal regions of each homodimer. These results deepen our understanding of the binding restraints of this CC MBS·LZ PKG-Iα low-affinity heterotetrameric complex and allow reevaluation of the role(s) of myosin light-chain phosphatase partner polypeptides in regulation of vascular smooth-muscle cell contractility.
[Mh] Termos MeSH primário: Proteína Quinase Dependente de GMP Cíclico Tipo I/química
Zíper de Leucina
Miosinas/química
[Mh] Termos MeSH secundário: Animais
Dicroísmo Circular
Interações Hidrofóbicas e Hidrofílicas
Espectroscopia de Ressonância Magnética
Camundongos
Simulação de Dinâmica Molecular
Músculo Liso Vascular/citologia
Ligação Proteica
Domínios Proteicos
Multimerização Proteica
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
Espectrofotometria Ultravioleta
Eletricidade Estática
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); EC 3.6.4.1 (Myosins)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170311
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.781260


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[PMID]:28062507
[Au] Autor:Friederich-Persson M; Nguyen Dinh Cat A; Persson P; Montezano AC; Touyz RM
[Ad] Endereço:From the Institute of Cardiovascular Medicine and Sciences, University of Glasgow, United Kingdom.
[Ti] Título:Brown Adipose Tissue Regulates Small Artery Function Through NADPH Oxidase 4-Derived Hydrogen Peroxide and Redox-Sensitive Protein Kinase G-1α.
[So] Source:Arterioscler Thromb Vasc Biol;37(3):455-465, 2017 Mar.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Biomedical interest in brown adipose tissue (BAT) has increased since the discovery of functionally active BAT in adult humans. Although white adipose tissue (WAT) influences vascular function, vascular effects of BAT are elusive. Thus, we investigated the regulatory role and putative vasoprotective effects of BAT, focusing on hydrogen peroxide, nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4), and redox-sensitive signaling. APPROACH AND RESULTS: Vascular reactivity was assessed in wild-type and Nox4-knockout mice (Nox4 ) by wire myography in the absence and presence of perivascular adipose tissue of different phenotypes from various adipose depots: (1) mixed WAT/BAT (inguinal adipose tissue) and (2) WAT (epididymal visceral fat) and BAT (intrascapular fat). In wild-type mice, epididymal visceral fat and perivascular adipose tissue increased EC to noradrenaline without affecting maximum contraction. BAT increased EC and significantly decreased maximum contraction, which were prevented by a hydrogen peroxide scavenger (polyethylene glycated catalase) and a specific cyclic GMP-dependent protein kinase G type-1α inhibitor (DT-3), but not by inhibition of endothelial nitric oxide synthase or guanylate cyclase. BAT induced dimerization of cyclic GMP-dependent protein kinase G type-1α and reduced phosphorylation of myosin light chain phosphatase subunit 1 and myosin light chain 20. BAT from Nox4-knockout mice displayed reduced hydrogen peroxide levels and no anticontractile effects. Perivascular adipose tissue from ß agonist-treated mice displayed browned perivascular adipose tissue and an increased anticontractile effect. CONCLUSIONS: We identify a novel vasoprotective action of BAT through an anticontractile effect that is mechanistically different to WAT. Specifically, BAT, via Nox4-derived hydrogen peroxide, induces cyclic GMP-dependent protein kinase G type-1α activation, resulting in reduced vascular contractility. BAT may constitute an interesting therapeutic target to restore vascular function and prevent vascular complications in cardiovascular diseases.
[Mh] Termos MeSH primário: Tecido Adiposo Marrom/enzimologia
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
Peróxido de Hidrogênio/metabolismo
Artérias Mesentéricas/enzimologia
NADPH Oxidases/metabolismo
Vasoconstrição
[Mh] Termos MeSH secundário: Tecido Adiposo Marrom/efeitos dos fármacos
Tecido Adiposo Branco/enzimologia
Animais
Relação Dose-Resposta a Droga
Ativação Enzimática
Feminino
Genótipo
Técnicas In Vitro
Masculino
Artérias Mesentéricas/efeitos dos fármacos
Camundongos Endogâmicos C57BL
Camundongos Knockout
NADPH Oxidase 4
NADPH Oxidases/deficiência
NADPH Oxidases/genética
Oxirredução
Comunicação Parácrina
Fenótipo
Transdução de Sinais
Vasoconstrição/efeitos dos fármacos
Vasoconstritores/farmacologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Vasoconstrictor Agents); BBX060AN9V (Hydrogen Peroxide); EC 1.6.3.- (NADPH Oxidase 4); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.- (Nox4 protein, mouse); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); EC 2.7.11.12 (Prkg1 protein, mouse)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170108
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.308659


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[PMID]:27980245
[Au] Autor:Ahmed KA; Zhang T; Ono K; Tsutsuki H; Ida T; Akashi S; Miyata K; Oike Y; Akaike T; Sawa T
[Ad] Endereço:Department of Pathology, University of Alabama at Birmingham.
[Ti] Título:Synthesis and Characterization of 8-Nitroguanosine 3',5'-Cyclic Monophosphorothioate Rp-Isomer as a Potent Inhibitor of Protein Kinase G1α.
[So] Source:Biol Pharm Bull;40(3):365-374, 2017 Mar 01.
[Is] ISSN:1347-5215
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinases (PKG) are kinases regulating diverse physiological functions including vascular smooth muscle relaxation, neuronal synaptic plasticity, and platelet activities. Certain PKG inhibitors, such as Rp-diastereomers of derivatives of guanosine 3',5'-cyclic monophosphorothioate (Rp-cGMPS), have been designed and used to study PKG-regulated cell signaling. 8-Nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP) is an endogenous cGMP derivative formed as a result of excess production of reactive oxygen species and nitric oxide. 8-Nitro-cGMP causes persistent activation of PKG1α through covalent attachment of cGMP moieties to cysteine residues of the enzyme (i.e., the process called protein S-guanylation). In this study, we synthesized a nitrated analogue of Rp-cGMPS, 8-nitroguanosine 3',5'-cyclic monophosphorothioate Rp-isomer (Rp-8-nitro-cGMPS), and investigated its effects on PKG1α activity. We synthesized Rp-8-nitro-cGMPS by reacting Rp-8-bromoguanosine 3',5'-cyclic monophosphorothioate (Rp-8-bromo-cGMPS) with sodium nitrite. Rp-8-Nitro-cGMPS reacted with the thiol compounds cysteine and glutathione to form Rp-8-thioalkoxy-cGMPS adducts to a similar extent as did 8-nitro-cGMP. As an important finding, a protein S-guanylation-like modification was clearly observed, by using Western blotting, in the reaction between recombinant PKG1α and Rp-8-nitro-cGMPS. Rp-8-Nitro-cGMPS inhibited PKG1α activity with an inhibitory constant of 22 µM in a competitive manner. An organ bath assay with mouse aorta demonstrated that Rp-8-nitro-cGMPS inhibited vascular relaxation induced by acetylcholine or 8-bromo-cGMP more than Rp-8-bromo-cGMPS did. These findings suggest that Rp-8-nitro-cGMPS inhibits PKG through induction of an S-guanylation-like modification by attaching the Rp-cGMPS moiety to the enzyme. Additional study is warranted to explore the potential application of Rp-8-nitro-cGMPS to biochemical and therapeutic research involving PKG1α activation.
[Mh] Termos MeSH primário: Proteína Quinase Dependente de GMP Cíclico Tipo I/antagonistas & inibidores
GMP Cíclico/análogos & derivados
Guanosina/análogos & derivados
Nitrocompostos/farmacologia
Tionucleotídeos/farmacologia
Vasodilatação/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilcolina
Animais
Aorta
GMP Cíclico/síntese química
GMP Cíclico/metabolismo
GMP Cíclico/farmacologia
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
Guanosina/metabolismo
Guanosina/farmacologia
Isomerismo
Masculino
Camundongos Endogâmicos C57BL
Nitrocompostos/metabolismo
Processamento de Proteína Pós-Traducional
Transdução de Sinais
Tionucleotídeos/síntese química
Tionucleotídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (8-nitroguanosine); 0 (8-nitroguanosine 3',5'-cyclic monophosphate); 0 (Nitro Compounds); 0 (Thionucleotides); 12133JR80S (Guanosine); 150418-07-8 (8-bromoguanosino-3',5'-cyclic monophosphorothioate); 31356-94-2 (8-bromocyclic GMP); 67736-26-9 (guanosine-3',5'-cyclic phosphorothioate); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); H2D2X058MU (Cyclic GMP); N9YNS0M02X (Acetylcholine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170328
[Lr] Data última revisão:
170328
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161217
[St] Status:MEDLINE
[do] DOI:10.1248/bpb.b16-00880


  9 / 308 MEDLINE  
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[PMID]:27914169
[Au] Autor:Campbell JC; VanSchouwen B; Lorenz R; Sankaran B; Herberg FW; Melacini G; Kim C
[Ad] Endereço:Structural and Computational Biology and Molecular Biophysics Program, Baylor College of Medicine, Houston, TX, USA.
[Ti] Título:Crystal structure of cGMP-dependent protein kinase Iß cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation.
[So] Source:FEBS Lett;591(1):221-230, 2017 Jan.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The R-diastereomer of phosphorothioate analogs of cGMP, Rp-cGMPS, is one of few known inhibitors of cGMP-dependent protein kinase I (PKG I); however, its mechanism of inhibition is currently not fully understood. Here, we determined the crystal structure of the PKG Iß cyclic nucleotide-binding domain (PKG Iß CNB-B), considered a 'gatekeeper' for cGMP activation, bound to Rp-cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iß CNB-B bound to Rp-cGMPS displays an apo-like structure with its helical domain in an open conformation. Comparison with the cAMP-dependent protein kinase regulatory subunit (PKA RIα) showed that this conformation resembles the catalytic subunit-bound inhibited state of PKA RIα more closely than the apo or Rp-cAMPS-bound conformations. These results suggest that Rp-cGMPS inhibits PKG I by stabilizing the inactive conformation of CNB-B.
[Mh] Termos MeSH primário: Apoenzimas/química
Apoenzimas/metabolismo
Proteína Quinase Dependente de GMP Cíclico Tipo I/química
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
GMP Cíclico/análogos & derivados
GMP Cíclico/metabolismo
Tionucleotídeos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Cristalografia por Raios X
GMP Cíclico/química
Proteína Quinase Dependente de GMP Cíclico Tipo I/antagonistas & inibidores
Estabilidade Enzimática
Cinética
Espectroscopia de Ressonância Magnética
Conformação Proteica
Domínios Proteicos
Estereoisomerismo
Tionucleotídeos/química
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Apoenzymes); 0 (Thionucleotides); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); H2D2X058MU (Cyclic GMP)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170523
[Lr] Data última revisão:
170523
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161204
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12505


  10 / 308 MEDLINE  
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[PMID]:27879251
[Au] Autor:Milewicz DM; Trybus KM; Guo DC; Sweeney HL; Regalado E; Kamm K; Stull JT
[Ad] Endereço:From the Department of Internal Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston (D.M.M., D.-c.G., E.R.); Department of Molecular Physiology and Biophysics, University of Vermont, Burlington (K.M.T.); Department of Pharmacology and Therapeutics, Universit
[Ti] Título:Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections.
[So] Source:Arterioscler Thromb Vasc Biol;37(1):26-34, 2017 Jan.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling contraction lead to the formation of aneurysms of the ascending thoracic aorta that predispose to life-threatening aortic dissections. Force generation by SMC requires ATP-dependent cyclic interactions between filaments composed of SMC-specific isoforms of α-actin (encoded by ACTA2) and myosin heavy chain (MYH11). ACTA2 and MYH11 mutations are predicted or have been shown to disrupt this cyclic interaction predispose to thoracic aortic disease. Movement of the myosin motor domain is controlled by phosphorylation of the regulatory light chain on the myosin filament, and loss-of-function mutations in the dedicated kinase for this phosphorylation, myosin light chain kinase (MYLK) also predispose to thoracic aortic disease. Finally, a mutation in the cGMP-activated protein kinase (PRKG1) results in constitutive activation of the kinase in the absence of cGMP, thus driving SMC relaxation in part through increased dephosphorylation of the regulatory light chain and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix through focal adhesions, and mutations in the major protein in the extracellular matrix, fibrillin-1, linking SMCs to the matrix also cause thoracic aortic disease in individuals with Marfan syndrome. Thus, disruption of the ability of the aortic SMC to generate force through the elastin-contractile units in response to pulsatile blood flow may be a primary driver for thoracic aortic aneurysms and dissections.
[Mh] Termos MeSH primário: Aneurisma Dissecante/fisiopatologia
Aneurisma da Aorta Torácica/fisiopatologia
Músculo Liso Vascular/fisiopatologia
Vasoconstrição
[Mh] Termos MeSH secundário: Actinas/genética
Actinas/metabolismo
Aneurisma Dissecante/genética
Aneurisma Dissecante/metabolismo
Aneurisma Dissecante/patologia
Animais
Aneurisma da Aorta Torácica/genética
Aneurisma da Aorta Torácica/metabolismo
Aneurisma da Aorta Torácica/patologia
Proteínas de Ligação ao Cálcio/genética
Proteínas de Ligação ao Cálcio/metabolismo
Proteína Quinase Dependente de GMP Cíclico Tipo I/genética
Proteína Quinase Dependente de GMP Cíclico Tipo I/metabolismo
Dilatação Patológica
Elastina/metabolismo
Marcadores Genéticos
Testes Genéticos
Hereditariedade
Seres Humanos
Mecanotransdução Celular
Músculo Liso Vascular/metabolismo
Músculo Liso Vascular/patologia
Mutação
Miócitos de Músculo Liso/metabolismo
Miócitos de Músculo Liso/patologia
Cadeias Pesadas de Miosina/genética
Cadeias Pesadas de Miosina/metabolismo
Quinase de Cadeia Leve de Miosina/genética
Quinase de Cadeia Leve de Miosina/metabolismo
Fenótipo
Fluxo Pulsátil
Vasoconstrição/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (ACTA2 protein, human); 0 (Actins); 0 (Calcium-Binding Proteins); 0 (Genetic Markers); 0 (MYH11 protein, human); 9007-58-3 (Elastin); EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinase Type I); EC 2.7.11.12 (PRKG1 protein, human); EC 2.7.11.18 (MYLK protein, human); EC 2.7.11.18 (Myosin-Light-Chain Kinase); EC 3.6.4.1 (Myosin Heavy Chains)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161124
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.116.303229



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