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Karim Roder Andreas A. Werdich Weiyan Li Man Liu Tae Yun Kim Louise E. Organ-Darling Karni S. Moshal Jung Min Hwang Yichun Lu Bum-Rak Choi Calum A. MacRae Gideon Koren 《The Journal of biological chemistry》2014,289(49):33730-33740
Two recent studies (Newton-Cheh, C. et al. (2009) Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat. Genet. 41, 399–406 and Pfeufer, A. et al. (2009) Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat. Genet. 41, 407–414) identified an association, with genome-wide significance, between a single nucleotide polymorphism within the gene encoding RING finger protein 207 (RNF207) and the QT interval. We sought to determine the role of RNF207 in cardiac electrophysiology. Morpholino knockdown of RNF207 in zebrafish embryos resulted in action potential duration prolongation, occasionally a 2:1 atrioventricular block, and slowing of conduction velocity. Conversely, neonatal rabbit cardiomyocytes infected with RNF207-expressing adenovirus exhibited shortened action potential duration. Using transfections of U-2 OS and HEK293 cells, Western blot analysis and immunocytochemistry data demonstrate that RNF207 and the human ether-a-go-go-related gene (HERG) potassium channel interact and colocalize. Furthermore, RNF207 overexpression significantly elevated total and membrane HERG protein and HERG-encoded current density by ∼30–50%, which was dependent on the intact N-terminal RING domain of RNF207. Finally, coexpression of RNF207 and HSP70 increased HERG expression compared with HSP70 alone. This effect was dependent on the C terminus of RNF207. Taken together, the evidence is strong that RNF207 is an important regulator of action potential duration, likely via effects on HERG trafficking and localization in a heat shock protein-dependent manner. 相似文献
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Rosenberger D Moshal KS Kartha GK Tyagi N Sen U Lominadze D Maldonado C Roberts AM Tyagi SC 《Archives of physiology and biochemistry》2006,112(4-5):219-227
Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) are associated with arrhythmogenesis and sudden cardiac death (SCD). Hcy decreases constitutive neuronal and endothelial nitric oxide (NO), and cardiac diastolic relaxation. Hcy increases the iNOS/NO, peroxynitrite, mitochondrial NADPH oxidase, and suppresses superoxide dismutase (SOD) and redoxins. Hcy activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) disrupt the normal pattern of cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling, leading to a pro-arrhythmic environment. The goal of this review is to elaborate the mechanism of Hcy-mediated iNOS/NO in E-M uncoupling and SCD. It is known that Hcy creates arrhythmogenic substrates (i.e. increase in collagen/elastin ratio and disruption in connexin-43) and exacerbates heart failure during chronic volume overload. Also, Hcy behaves as an agonist to N-methyl-D-aspartate (NMDA, an excitatory neurotransmitter) receptor-1, and blockade of NMDA-R1 reduces the increase in heart rate-evoked by NMDA-analog and reduces SCD. This review suggest that Hcy increases iNOS/NO, superoxide, metalloproteinase activity, and disrupts connexin-43, exacerbates endothelial-myocyte uncoupling and cardiac failure secondary to inducing NMDA-R1. 相似文献
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Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway 总被引:6,自引:0,他引:6
Moshal KS Sen U Tyagi N Henderson B Steed M Ovechkin AV Tyagi SC 《American journal of physiology. Cell physiology》2006,290(3):C883-C891
Homocysteine (Hcy) induces matrix metalloproteinase (MMP)-9 in microvascular endothelial cells (MVECs). We hypothesized that the ERK1/2 signaling pathway is involved in Hcy-mediated MMP-9 expression. In cultured MVECs, Hcy induced activation of ERK, which was blocked by PD-98059 and U0126 (MEK inhibitors). Pretreatment with BAPTA-AM, staurosporine (PKC inhibitor), or Gö6976 (specific inhibitor for Ca2+-dependent PKC) abrogated ERK phosphorylation, suggesting the role of Ca2+ and Ca2+-dependent PKC in Hcy-induced ERK activation. ERK phosphorylation was suppressed by pertussis toxin (PTX), suggesting the involvement of G protein-coupled receptors (GPCRs) in initiating signal transduction by Hcy and leading to ERK activation. Pretreatment of MVECs with genistein, BAPTA-AM, or thapsigargin abrogated Hcy-induced ERK activation, suggesting the involvement of the PTK pathway in Hcy-induced ERK activation, which was mediated by intracellular Ca2+ pool depletion. ERK activation was attenuated by preincubation with N-acetylcysteine (NAC) and SOD, suggesting the role of oxidation in Hcy-induced ERK activation. Pretreatment with an ERK1/2 blocker (PD-98059), staurosporine, folate, or NAC modulated Hcy-induced MMP-9 activation as measured using zymography. Our results provide evidence that Hcy triggers the PTX-sensitive ERK1/2 signaling pathway, which is involved in the regulation of MMP-9 in MVECs. calcium signaling; protein kinase C; Src; G protein-coupled receptor; nonreceptor tyrosine kinase; protein Gi; protein Gq; protein tyrosine kinase 2; microvascular endothelial cell; cardiovascular remodeling 相似文献
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Cdc42 and noncanonical Wnt signal transduction pathways cooperate to promote cell polarity 总被引:1,自引:0,他引:1 下载免费PDF全文
Scratch-induced disruption of cultured monolayers induces polarity in front row cells that can be visualized by spatially localized polymerization of actin at the front of the cell and reorientation of the centrosome/Golgi to face the leading edge. We previously reported that centrosomal reorientation and microtubule polarization depend on a Cdc42-regulated signal transduction pathway involving activation of the Par6/aPKC complex followed by inhibition of GSK-3beta and accumulation of the adenomatous polyposis coli (APC) protein at the plus ends of leading-edge microtubules. Using monolayers of primary rodent embryo fibroblasts, we show here that dishevelled (Dvl) and axin, two major components of the Wnt signaling pathway are required for centrosome reorientation and that Wnt5a is required for activation of this pathway. We conclude that disruption of cell-cell contacts leads to the activation of a noncanonical Wnt/dishevelled signal transduction pathway that cooperates with Cdc42/Par6/aPKC to promote polarized reorganization of the microtubule cytoskeleton. 相似文献
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Ion Content of the Halotolerant Alga Dunaliella salina 总被引:3,自引:0,他引:3
The intracellular concentration of the major ions in Dunaliellasalina cells were determined, following the removal of extracellularions by ion-exchange minicolumns. Log phase cells, grown inmedia containing 14 molar NaCl, contained 3050mM chloride and 200350 mM magnesium (5 mM in medium).Phosphorus, which is present intracellularly mostly as polyphosphate,was present in amounts of 60100 fmoles per cell, equivalentto a concentration of 6001,000 mM (0.2 mM in medium).Previous data indicated that such cells contained 2040mM Na+, 150300mM K+, 20mM SO24, and very low concentrationsof Ca2+ and charged nitrogenous compounds. Mg2+ and K+ seemto serve as the major counter ions for the intracellular negativecharge present in the massively accumulated polyphosphates.The former accounts for about 2/3 of the required positive charge.This is supported by the observation that limitation in thephosphate or K+ supply in the medium lead to a parallel decreasein the accumulation of intracellular phosphorus, Mg2+ or K+.
1Present address: Department of Vegetables, The Volcani Center,Bet-Dagan 50250, Israel. (Received June 13, 1988; Accepted August 25, 1988) 相似文献
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Human neutrophil nuclei typically consist of three of four large heterochromatic lobes joined by thin, DNA-containing filaments.
In addition, some lobes exhibit appendages of various sizes and shapes. Classical genetic and cytological studies suggest
that some appendages contain specific chromsomes. The studies reported here provide the first detailed analysis of the spatial
relationship between individual chromosomes and recognizable structures in neutrophil nuclei using fluorescent in situ hybridization.
Analysis of DNA sequences in chromosomes 2, 18, X, and Y demonstrate that specific lobes in a population of neutrophil nuclei
do not have a fied chromosome content. This result implies that chromosomes partition randomly among lobes during neutrophil
differentiation. However, neutrophil nuclear topography is not entirely fortuitous. For instance, none of the sequences probed
in this study mapped to a filament and most centromeres lie in clusters near the nuclear periphery. In addition, one of the
X chromosome centromeres in females and the Y chromosome centromere in males consistently associate with specific nuclear
appendages found in a subset of neutrophil nuclei. Chromosomes 2 and 18 occupy discrete nd separate territories within individual
lobes and neither territory ever extends into a filament. Surprisingly, the sizes of these territories are not proportional
to chromosome length, suggesting that individual neutrophil chromosomes vary in their degree of compaction. These results
are discussed in the light of models that attempt to explain nuclear morphology in terms of chromosome spatial organization.
Received: 10 April 1997 / Accepted: 14 April 1997 相似文献