排序方式: 共有92条查询结果,搜索用时 31 毫秒
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Sameer Ather Jonathan L. Respress Na Li Xander H.T. Wehrens 《生物化学与生物物理学报:疾病的分子基础》2013,1832(12):2425-2431
Sarcoplasmic reticulum (SR) Ca2 + release plays an essential role in mediating cardiac myocyte contraction. Depolarization of the plasma membrane results in influx of Ca2 + through l-type Ca2 + channels (LTCCs) that in turn triggers efflux of Ca2 + from the SR through ryanodine receptor type-2 channels (RyR2). This process known as Ca2 +-induced Ca2 +release (CICR) occurs within the dyadic region, where the adjacent transverse (T)-tubules and SR membranes allow RyR2 clusters to release SR Ca2 + following Ca2 + influx through adjacent LTCCs. SR Ca2 + released during systole binds to troponin-C and initiates actin–myosin cross-bridging, leading to muscle contraction. During diastole, the cytosolic Ca2 + concentration is restored by the resequestration of Ca2 + into the SR by SR/ER Ca2 +-ATPase (SERCA2a) and by the extrusion of Ca2 + via the Na+/Ca2 +-exchanger (NCX1). This whole process, entitled excitation–contraction (EC) coupling, is highly coordinated and determines the force of contraction, providing a link between the electrical and mechanical activities of cardiac muscle. In response to heart failure (HF), the heart undergoes maladaptive changes that result in depressed intracellular Ca2 + cycling and decreased SR Ca2 + concentrations. As a result, the amplitude of CICR is reduced resulting in less force production during EC coupling. In this review, we discuss the specific proteins that alter the regulation of Ca2 + during HF. In particular, we will focus on defects in RyR2-mediated SR Ca2 + release. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions. 相似文献
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Rajesh Jayachandran Xiaolong Liu Somdeb BoseDasgupta Philipp Müller Chun-Lei Zhang Despina Moshous Vera Studer Jacques Schneider Christel Genoud Catherine Fossoud Frédéric Gambino Malik Khelfaoui Christian Müller Deborah Bartholdi Helene Rossez Michael Stiess Xander Houbaert Rolf Jaussi Daniel Frey Richard A. Kammerer Xavier Deupi Jean-Pierre de Villartay Andreas Lüthi Yann Humeau Jean Pieters 《PLoS biology》2014,12(3)
Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic–AMP–protein kinase A–dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1–deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes. 相似文献
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Fernanda Molognoni Adriana T Cruz Fabiana M Meliso Alice S Morais Camila F Souza Patrícia Xander Jared M Bischof Fabrício F Costa Marcelo B Soares Gangning Liang Peter A Jones Miriam G Jasiulionis 《Epigenetics》2011,6(4):450-464
Melanoma progression requires deregulation of gene expression by currently uncharacterized epigenetic mechanisms. A mouse model based on changes in cell microenvironment was developed by our group to study melanocyte malignant transformation. Melanoma cell lines (4C11− and 4C11+) were obtained as result of 5 sequential anchorage blockades of non-tumorigenic melan-a melanocytes. Melan-a cells submitted to 4 de-adhesion cycles were also established (4C), are non-tumorigenic and represent an intermediary phase of tumor progression. The aim of this work was to identify factors contributing to epigenetic modifications in early and later phases of malignant transformation induced by anchorage impediment. Epigenetic alterations occur early in tumorigenesis; 4C cell line shows changes in global and gene-specific DNA methylation and histone marks. Many histone modifications differ between melan-a, 4C, 4C11− (non-metastatic melanoma cell line) and 4C11+ (metastatic melanoma cell line) which could be associated with changes in gene and microRNA expression. These epigenetic alterations seem to play a key role in malignant transformation since melanocytes treated with 5-Aza-2′-deoxycytidine before each anchorage blockade do not transform. Some epigenetic changes seem to be also responsible for the maintenance of malignant phenotype, since melanoma cell lines (4C11− and 4C11+) treated in vitro with 5-Aza-2′-deoxycytidine or Trichostatin A showed reduction of tumor growth in vivo. Changes in gene expression reflecting cell adaptation to new environment were also observed. We propose a model in which sustained microenvironmental stress in melanocytes results in epigenetic reprogramming. Thus, after adaptation, cells may acquire epigenetic marks that could contribute to the establishment of a malignant phenotype.Key words: anchorage blockade, sustained stress, pluripotency, epigenetic reprogramming, malignant melanoma 相似文献
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Salicylamide inhibitors of influenza virus fusion 总被引:2,自引:0,他引:2
Combrink KD Gulgeze HB Yu KL Pearce BC Trehan AK Wei J Deshpande M Krystal M Torri A Luo G Cianci C Danetz S Tiley L Meanwell NA 《Bioorganic & medicinal chemistry letters》2000,10(15):1649-1652
Structural variation of the quinolizidine heterocycle of the influenza fusion inhibitor BMY-27709 was examined by several topological dissections in order to illuminate the critical features of the ring system. This exercise resulted in the identification of a series of synthetically more accessible decahydroquinolines that retained the structural elements of BMY-27709 important for antiviral activity. The 2-methyl-cis-decahydroquinoline 6f was the most potent influenza inhibitor identified that demonstrated an EC50 of 90 ng/mL in a plaque reduction assay. 相似文献
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Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias 总被引:12,自引:0,他引:12
Lehnart SE Wehrens XH Reiken S Warrier S Belevych AE Harvey RD Richter W Jin SL Conti M Marks AR 《Cell》2005,123(1):25-35
Phosphodiesterases (PDEs) regulate the local concentration of 3',5' cyclic adenosine monophosphate (cAMP) within cells. cAMP activates the cAMP-dependent protein kinase (PKA). In patients, PDE inhibitors have been linked to heart failure and cardiac arrhythmias, although the mechanisms are not understood. We show that PDE4D gene inactivation in mice results in a progressive cardiomyopathy, accelerated heart failure after myocardial infarction, and cardiac arrhythmias. The phosphodiesterase 4D3 (PDE4D3) was found in the cardiac ryanodine receptor (RyR2)/calcium-release-channel complex (required for excitation-contraction [EC] coupling in heart muscle). PDE4D3 levels in the RyR2 complex were reduced in failing human hearts, contributing to PKA-hyperphosphorylated, "leaky" RyR2 channels that promote cardiac dysfunction and arrhythmias. Cardiac arrhythmias and dysfunction associated with PDE4 inhibition or deficiency were suppressed in mice harboring RyR2 that cannot be PKA phosphorylated. These data suggest that reduced PDE4D activity causes defective RyR2-channel function associated with heart failure and arrhythmias. 相似文献
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Phenotypical temperature adaptation of protein synthesis in wheat seedlings: time curves for readaptation 下载免费PDF全文
Optimum temperature and temperature coefficient of protein synthesis in young wheat plants exhibit phenotypical temperature adaptation. In plants grown for 2 days at either chilling (4 C), medium (20 C), or high (36 C) temperature the respective values are: 27 C and 14.2 kilocalories per mole, 31 C and 18.2 kilocalories per mole, 35 C and 23.6 kilocalories per mole, based on in vivo [14C]leucine incorporation into total protein. The validity of the [14C]leucine incubation method has been confirmed by double-labeling experiments. Readaptation time curves are complex: the optimum temperature parameter readjusts within approximately 4 hours to an altered temperature regime, whereas the temperature coefficient needs between 4 and 96 hours for complete readaptation—depending on the temperature conditions prior to the temperature shift. Heat-preadapted plants need a recovery period at medium temperature to regain their cold adaptability with respect to optimum temperature. Cycloheximide (30 micrograms per milliliter) reduces [14C]leucine incorporation into protein by 85%, thus indicating that predominantly the cytoplasmic 80S system of protein synthesis is involved in temperature adaptation. 相似文献
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Yu KL Sin N Civiello RL Wang XA Combrink KD Gulgeze HB Venables BL Wright JJ Dalterio RA Zadjura L Marino A Dando S D'Arienzo C Kadow KF Cianci CW Li Z Clarke J Genovesi EV Medina I Lamb L Colonno RJ Yang Z Krystal M Meanwell NA 《Bioorganic & medicinal chemistry letters》2007,17(4):895-901
A series of benzimidazole-based inhibitors of respiratory syncytial virus (RSV) fusion were optimized for antiviral potency, membrane permeability and metabolic stability in human liver microsomes. 1-Cyclopropyl-1,3-dihydro-3-[[1-(4-hydroxybutyl)-1H-benzimidazol-2-yl]methyl]-2H-imidazo[4,5-c]pyridin-2-one (6m, BMS-433771) was identified as a potent RSV inhibitor demonstrating good bioavailability in the mouse, rat, dog and cynomolgus monkey that demonstrated antiviral activity in the BALB/c and cotton rat models of infection following oral administration. 相似文献