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L V Zingman A E Alekseev D M Hodgson-Zingman A Terzic 《Journal of applied physiology》2007,103(5):1888-1893
The cardiovascular system operates under a wide scale of demands, ranging from conditions of rest to extreme stress. How the heart muscle matches rates of ATP production with utilization is an area of active investigation. ATP-sensitive potassium (K(ATP)) channels serve a critical role in the orchestration of myocardial energetic well-being. K(ATP) channel heteromultimers consist of inwardly-rectifying K(+) channel 6.2 and ATP-binding cassette sulfonylurea receptor 2A that translates local ATP/ADP levels, set by ATPases and phosphotransfer reactions, to the channel pore function. In cells in which the mobility of metabolites between intracellular microdomains is limited, coupling of phosphotransfer pathways with K(ATP) channels permits a high-fidelity transduction of nucleotide fluxes into changes in membrane excitability, matching energy demands with metabolic resources. This K(ATP) channel-dependent optimization of cardiac action potential duration preserves cellular energy balance at varying workloads. Mutations of K(ATP) channels result in disruption of the nucleotide signaling network and generate a stress-vulnerable phenotype with excessive susceptibility to injury, development of cardiomyopathy, and arrhythmia. Solving the mechanisms underlying the integration of K(ATP) channels into the cellular energy network will advance the understanding of endogenous cardioprotection and the development of strategies for the management of cardiovascular injury and disease progression. 相似文献
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Pucar D Dzeja PP Bast P Gumina RJ Drahl C Lim L Juranic N Macura S Terzic A 《Molecular and cellular biochemistry》2004,256(1-2):281-289
Brief hypoxia or ischemia perturbs energy metabolism inducing paradoxically a stress-tolerant state, yet metabolic signals that trigger cytoprotection remain poorly understood. To evaluate bioenergetic rearrangements, control and hypoxic hearts were analyzed with 18O-assisted 31P NMR and 1H NMR spectroscopy. The 18O-induced isotope shift in the 31P NMR spectrum of CrP, betaADP and betaATP was used to quantify phosphotransfer fluxes through creatine kinase and adenylate kinase. This analysis was supplemented with determination of energetically relevant metabolites in the phosphomonoester (PME) region of 31P NMR spectra, and in both aromatic and aliphatic regions of 1H NMR spectra. In control conditions, creatine kinase was the major phosphotransfer pathway processing high-energy phosphoryls between sites of ATP consumption and ATP production. In hypoxia, creatine kinase flux was dramatically reduced with a compensatory increase in adenylate kinase flux, which supported heart energetics by regenerating and transferring beta- and gamma-phosphoryls of ATP. Activation of adenylate kinase led to a build-up of AMP, IMP and adenosine, molecules involved in cardioprotective signaling. 31P and 1H NMR spectral analysis further revealed NADH and H+ scavenging by alpha-glycerophosphate dehydrogenase (alphaGPDH) and lactate dehydrogenase contributing to maintained glycolysis under hypoxia. Hypoxia-induced accumulation of alpha-glycerophosphate and nucleoside 5'-monophosphates, through alphaGPDH and adenylate kinase reactions, respectively, was mapped within the increased PME signal in the 31P NMR spectrum. Thus, 18O-assisted 31P NMR combined with 1H NMR provide a powerful approach in capturing rearrangements in cardiac bioenergetics, and associated metabolic signaling that underlie the cardiac adaptive response to stress. 相似文献
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Stoll C Fischbach M Terzic J Alembik Y Vuillemin MO Mornet E 《Genetic counseling (Geneva, Switzerland)》2002,13(3):289-295
Hypophosphatasia is a rare autosomal recessive inborn error of metabolism characterized by a defective bone mineralisation and deficiency of serum and tissue liver/bone/kidney alkaline phosphatase activity. We report the characterisation of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutation in a patient affected by infantile hypophosphatasia. This boy was the first child of non affected, non related parents. At 1 month of age he presented with palsy of the left upper limb with hypotonia. Length was - 2SD. The anterior fontanel was large. There was a markedly decreased ossification of all bones. All limbs were shortened. Ultrasonographic examination of the kidneys showed nephrocalcinosis. Level of alkaline phosphatases was decreased in the child as well as in the parents. Bone density was decreased. At 2 years of age development was delayed. Weight was - 3,5 SD and OFC - 3SD. The child had craniosynostosis. Molecular studies showed 2 missense mutations, both in exon 6 of the TNSALP gene. 相似文献
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Malej Alenka; Mozetic Patricija; Turk Valentina; Terzic Senka; Ahel Marijan; Cauwet Gustave 《Journal of plankton research》2003,25(8):949-966
This study examined the partitioning of organic matter intoparticulate organic carbon (POC) and dissolved organic carbon(DOC) pools in nutrient-enriched enclosures containing naturalplankton from the Gulf of Trieste (northern Adriatic), an areaaffected by mucilage. The strategy of nutrient additions wasto introduce a pulse of new nutrients in concentrations thatmimic natural inputs and to survey community structure and organicmatter fluxes long enough so that plankton became nutrient-limited.Maximal bacterial biomass attained roughly double the initialvalue, while autotrophic carbon increased by nearly an orderof magnitude. The microflagellate-dominated community releasedmore DOC per unit biomass (5.5 ± 7.2 to 50.6 ±28.0 µg C µg Chl a-1 day-1 versus 3.4 ± 3.4to 10.8 ± 4.6 µg C µg Chl a-1 day-1 for diatom-dominatedphytoplankton), POC increase was modest (~300 µg C l-1)and there was little change in DOC. Organic carbon partitioningduring two experiments in which diatoms prevailed was dominatedby POC (>800 µg C l-1) in the exponential growth phasewith an increasing contribution of particulate carbohydratesthat paralleled gradual nutrient depletion. Transition to thestationary phase and the decay of autotrophic communities wereaccompanied by the net accumulation of a carbohydrate-rich DOC. 相似文献
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The role of nuclear DNA (nDNA)-encoded proteins in the regulation of mitochondrial fission and fusion has been documented, yet the role of mitochondrial DNA (mtDNA) and encoded proteins in mitochondrial biogenesis remains unknown. Long-term treatment of a lymphoblastoid cell line Molt-4 with ethidium bromide generated mtDNA-deficient rho0 mutants. Depletion of mtDNA in rho0 cells produced functional and morphological changes in mitochondria without affecting the nuclear genome and encoded proteins. Indeed, the gene encoding subunit II of mitochondrial cytochrome c oxidase (COX II), a prototypical mitochondrial gene, was reduced in rho0 mutants blunting the activity of mitochondrial cytochrome coxidase. Yet, the amount of the nuclear beta-actin gene and the activity of citrate synthase, a mitochondrial matrix enzyme encoded by nDNA, remained unaffected in rho0 cells. Loss of mtDNA in rho0 cells was associated with significant distortion of mitochondrial structure, decreased electron density of the matrix and disorganized inner and outer membranes, resulting in the appearance of 'ghost-like' mitochondria. However, the number of mitochondria-like structures was not significantly different between mtDNA-deficient and parental cells. Thus, we conclude that cells lacking mtDNA still generate mitochondrial scaffolds, albeit with aberrant function. 相似文献
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Hodgson DM Zingman LV Kane GC Perez-Terzic C Bienengraeber M Ozcan C Gumina RJ Pucar D O'Coclain F Mann DL Alekseev AE Terzic A 《The EMBO journal》2003,22(8):1732-1742
ATP-sensitive potassium (K(ATP)) channels are required for maintenance of homeostasis during the metabolically demanding adaptive response to stress. However, in disease, the effect of cellular remodeling on K(ATP) channel behavior and associated tolerance to metabolic insult is unknown. Here, transgenic expression of tumor necrosis factor alpha induced heart failure with typical cardiac structural and energetic alterations. In this paradigm of disease remodeling, K(ATP) channels responded aberrantly to metabolic signals despite intact intrinsic channel properties, implicating defects proximal to the channel. Indeed, cardiomyocytes from failing hearts exhibited mitochondrial and creatine kinase deficits, and thus a reduced potential for metabolic signal generation and transmission. Consequently, K(ATP) channels failed to properly translate cellular distress under metabolic challenge into a protective membrane response. Failing hearts were excessively vulnerable to metabolic insult, demonstrating cardiomyocyte calcium loading and myofibrillar contraction banding, with tolerance improved by K(ATP) channel openers. Thus, disease-induced K(ATP) channel metabolic dysregulation is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy. 相似文献
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Alexey E. Alekseev Peter A. Brady Andre Terzic 《The Journal of general physiology》1998,111(2):381-394
The mechanism by which ATP-sensitive K+ (KATP) channels open in the presence of inhibitory concentrations of ATP remains unknown. Herein, using a four-state kinetic model, we found that the nucleotide diphosphate UDP directed cardiac KATP channels to operate within intraburst transitions. These transitions are not targeted by ATP, nor the structurally unrelated sulfonylurea glyburide, which inhibit channel opening by acting on interburst transitions. Therefore, the channel remained insensitive to ATP and glyburide in the presence of UDP. “Rundown” of channel activity decreased the efficacy with which UDP could direct and maintain the channel to operate within intraburst transitions. Under this condition, the channel was sensitive to inhibition by ATP and glyburide despite the presence of UDP. This behavior of the KATP channel could be accounted for by an allosteric model of ligand-channel interaction. Thus, the response of cardiac KATP channels towards inhibitory ligands is determined by the relative lifetime the channel spends in a ligand-sensitive versus -insensitive state. Interconversion between these two conformational states represents a novel basis for KATP channel opening in the presence of inhibitory concentrations of ATP in a cardiac cell. 相似文献
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Evidence for Direct Physical Association between a K+ Channel (Kir6.2) and an ATP-Binding Cassette Protein (SUR1) Which Affects Cellular Distribution and Kinetic Behavior of an ATP-Sensitive K+ Channel
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Eva Lorenz Alexey E. Alekseev Grigory B. Krapivinsky Antonio J. Carrasco David E. Clapham Andre Terzic 《Molecular and cellular biology》1998,18(3):1652-1659
Structurally unique among ion channels, ATP-sensitive K+ (KATP) channels are essential in coupling cellular metabolism with membrane excitability, and their activity can be reconstituted by coexpression of an inwardly rectifying K+ channel, Kir6.2, with an ATP-binding cassette protein, SUR1. To determine if constitutive channel subunits form a physical complex, we developed antibodies to specifically label and immunoprecipitate Kir6.2. From a mixture of Kir6.2 and SUR1 in vitro-translated proteins, and from COS cells transfected with both channel subunits, the Kir6.2-specific antibody coimmunoprecipitated 38- and 140-kDa proteins corresponding to Kir6.2 and SUR1, respectively. Since previous reports suggest that the carboxy-truncated Kir6.2 can form a channel independent of SUR, we deleted 114 nucleotides from the carboxy terminus of the Kir6.2 open reading frame (Kir6.2ΔC37). Kir6.2ΔC37 still coimmunoprecipitated with SUR1, suggesting that the distal carboxy terminus of Kir6.2 is unnecessary for subunit association. Confocal microscopic images of COS cells transfected with Kir6.2 or Kir6.2ΔC37 and labeled with fluorescent antibodies revealed unique honeycomb patterns unlike the diffuse immunostaining observed when cells were cotransfected with Kir6.2-SUR1 or Kir6.2ΔC37-SUR1. Membrane patches excised from COS cells cotransfected with Kir6.2-SUR1 or Kir6.2ΔC37-SUR1 exhibited single-channel activity characteristic of pancreatic KATP channels. Kir6.2ΔC37 alone formed functional channels with single-channel conductance and intraburst kinetic properties similar to those of Kir6.2-SUR1 or Kir6.2ΔC37-SUR1 but with reduced burst duration. This study provides direct evidence that an inwardly rectifying K+ channel and an ATP-binding cassette protein physically associate, which affects the cellular distribution and kinetic behavior of a KATP channel. 相似文献