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Enantioselective Protein-Sterol Interactions Mediate Regulation of Both Prokaryotic and Eukaryotic Inward Rectifier K+ Channels by Cholesterol  [PDF]
Nazzareno D'Avanzo,Krzysztof Hyrc,Decha Enkvetchakul,Douglas F. Covey,Colin G. Nichols
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019393
Abstract: Cholesterol is the major sterol component of all mammalian cell plasma membranes and plays a critical role in cell function and growth. Previous studies have shown that cholesterol inhibits inward rectifier K+ (Kir) channels, but have not distinguished whether this is due directly to protein-sterol interactions or indirectly to changes in the physical properties of the lipid bilayer. Using purified bacterial and eukaryotic Kir channels reconstituted into liposomes of controlled lipid composition, we demonstrate by 86Rb+ influx assays that bacterial Kir channels (KirBac1.1 and KirBac3.1) and human Kir2.1 are all inhibited by cholesterol, most likely by locking the channels into prolonged closed states, whereas the enantiomer, ent-cholesterol, does not inhibit these channels. These data indicate that cholesterol regulates Kir channels through direct protein-sterol interactions likely taking advantage of an evolutionarily conserved binding pocket.
Characterization of the chicken inward rectifier K+ channel IRK1/Kir2.1 gene
Hideki Mutai, Lawrence C Kenyon, Emily Locke, Nami Kikuchi, John Oberholtzer
BMC Genomics , 2004, DOI: 10.1186/1471-2164-5-90
Abstract: We cloned and characterized the 5'-flanking region of cIRK1. cIRK1 contains two exons with splice sites in the 5'-untranslated region, a structure similar to mouse and human orthologs. cIRK1 has multiple transcription initiation sites, a feature also seen in mouse. However, while the chicken and mouse promoter regions share many regulatory motifs, cIRK1 possesses a GC-richer promoter and a putative TATA box, which appears to positively regulate gene expression. We report here the identification of several candidate cell/tissue specific cIRK1 regulatory domains by comparing promoter activities in expressing (Qm7) and non-expressing (DF1) cells using in vitro transcription assays.While multiple transcription initiation sites and the combinatorial function of several domains in activating cIRK1 expression are similar to those seen in mKir2.1, the cIRK1 promoter differs by the presence of a putative TATA box. In addition, several domains that regulate the gene's expression differentially in muscle (Qm7) and fibroblast cells (DF1) were identified. These results provide fundamental data to analyze cIRK1 transcriptional mechanisms. The control elements identified here may provide clues to the tissue-specific expression of this K+ channel.The inward rectifier potassium channel IRK1/Kir2.1 helps controls cell excitability through setting the resting membrane potential [1]. Its dominant role of inward rectification for the normal function of skeletal and cardiac muscles is shown by the complete loss of inward rectifying current and K+-induced dilations in arterial myocytes from Kir2.1 knockout mice [2] and periodic paralysis, and by cardiac arrhythmias in Anderson's syndrome caused by point mutation of human Kir2.1 [3].Kir2.1 expression is detected in excitable cells in brain, heart, and skeletal muscle in both mouse and chick [4-8]. In addition, chicken IRK1 (cIRK1) is expressed in the cochlea [8], a feature not observed in mammals [9,10]. In this report, we first analyzed c
Pharmacological Validation of an Inward-Rectifier Potassium (Kir) Channel as an Insecticide Target in the Yellow Fever Mosquito Aedes aegypti  [PDF]
Matthew F. Rouhier, Rene Raphemot, Jerod S. Denton, Peter M. Piermarini
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0100700
Abstract: Mosquitoes are important disease vectors that transmit a wide variety of pathogens to humans, including those that cause malaria and dengue fever. Insecticides have traditionally been deployed to control populations of disease-causing mosquitoes, but the emergence of insecticide resistance has severely limited the number of active compounds that are used against mosquitoes. Thus, to improve the control of resistant mosquitoes there is a need to identify new insecticide targets and active compounds for insecticide development. Recently we demonstrated that inward rectifier potassium (Kir) channels and small molecule inhibitors of Kir channels offer promising new molecular targets and active compounds, respectively, for insecticide development. Here we provide pharmacological validation of a specific mosquito Kir channel (AeKir1) in the yellow fever mosquito Aedes aegypti. We show that VU590, a small-molecule inhibitor of mammalian Kir1.1 and Kir7.1 channels, potently inhibits AeKir1 but not another mosquito Kir channel (AeKir2B) in vitro. Moreover, we show that a previously identified inhibitor of AeKir1 (VU573) elicits an unexpected agonistic effect on AeKir2B in vitro. Injection of VU590 into the hemolymph of adult female mosquitoes significantly inhibits their capacity to excrete urine and kills them within 24 h, suggesting a mechanism of action on the excretory system. Importantly, a structurally-related VU590 analog (VU608), which weakly blocks AeKir1 in vitro, has no significant effects on their excretory capacity and does not kill mosquitoes. These observations suggest that the toxic effects of VU590 are associated with its inhibition of AeKir1.
The Conformational Transition Pathways of ATP-Binding Cassette Transporter BtuCD Revealed by Targeted Molecular Dynamics Simulation  [PDF]
Jingwei Weng,Kangnian Fan,Wenning Wang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0030465
Abstract: BtuCD is a member of the ATP-binding cassette transporters in Escherichia coli that imports vitamin B12 into the cell by utilizing the energy of ATP hydrolysis. Crystal structures of BtuCD and its homologous protein HI1470/1 in various conformational states support the “alternating access” mechanism which proposes the conformational transitions of the substrate translocation pathway at transmembrane domain (TMD) between the outward-facing and inward-facing states. The conformational transition at TMD is assumed to couple with the movement of the cytoplasmic nucleotide-binding domains (NBDs) driven by ATP hydrolysis/binding. In this study, we performed targeted molecular dynamics (MD) simulations to explore the atomic details of the conformational transitions of BtuCD importer. The outward-facing to inward-facing (O→I) transition was found to be initiated by the conformational movement of NBDs. The subsequent reorientation of the substrate translocation pathway at TMD began with the closing of the periplasmic gate, followed by the opening of the cytoplamic gate in the last stage of the conformational transition due to the extensive hydrophobic interactions at this region, consistent with the functional requirement of unidirectional transport of the substrates. The reverse inward-facing to outward-facing (I→O) transition was found to exhibit intrinsic diversity of the conformational transition pathways and significant structural asymmetry, suggesting that the asymmetric crystal structure of BtuCD-F is an intermediate state in this process.
Discovery, Characterization, and Structure–Activity Relationships of an Inhibitor of Inward Rectifier Potassium (Kir) Channels with Preference for Kir2.3, Kir3.X, and Kir7.1  [PDF]
Rene Raphemot,C. David Weaver,Jerod S. Denton
Frontiers in Pharmacology , 2011, DOI: 10.3389/fphar.2011.00075
Abstract: The inward rectifier family of potassium (Kir) channels is comprised of at least 16 family members exhibiting broad and often overlapping cellular, tissue, or organ distributions. The discovery of disease-causing mutations in humans and experiments on knockout mice has underscored the importance of Kir channels in physiology and in some cases raised questions about their potential as drug targets. However, the paucity of potent and selective small-molecule modulators targeting specific family members has with few exceptions mired efforts to understand their physiology and assess their therapeutic potential. A growing body of evidence suggests that G protein-coupled inward rectifier K (GIRK) channels of the Kir3.X subfamily may represent novel targets for the treatment of atrial fibrillation. In an effort to expand the molecular pharmacology of GIRK, we performed a thallium (Tl+) flux-based high-throughput screen of a Kir1.1 inhibitor library for modulators of GIRK. One compound, termed VU573, exhibited 10-fold selectivity for GIRK over Kir1.1 (IC50 = 1.9 and 19 μM, respectively) and was therefore selected for further study. In electrophysiological experiments performed on Xenopus laevis oocytes and mammalian cells, VU573 inhibited Kir3.1/3.2 (neuronal GIRK) and Kir3.1/3.4 (cardiac GIRK) channels with equal potency and preferentially inhibited GIRK, Kir2.3, and Kir7.1 over Kir1.1 and Kir2.1.Tl+ flux assays were established for Kir2.3 and the M125R pore mutant of Kir7.1 to support medicinal chemistry efforts to develop more potent and selective analogs for these channels. The structure–activity relationships of VU573 revealed few analogs with improved potency, however two compounds retained most of their activity toward GIRK and Kir2.3 and lost activity toward Kir7.1. We anticipate that the VU573 series will be useful for exploring the physiology and structure–function relationships of these Kir channels.
Cation Diffusion Facilitators Transport Initiation and Regulation Is Mediated by Cation Induced Conformational Changes of the Cytoplasmic Domain  [PDF]
Natalie Zeytuni, René Uebe, Michal Maes, Geula Davidov, Michal Baram, Oliver Raschdorf, Merav Nadav-Tsubery, Sofiya Kolusheva, Ronit Bitton, Gil Goobes, Assaf Friedler, Yifat Miller, Dirk Schüler, Raz Zarivach
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092141
Abstract: Cation diffusion facilitators (CDF) are part of a highly conserved protein family that maintains cellular divalent cation homeostasis in all domains of life. CDF's were shown to be involved in several human diseases, such as Type-II diabetes and neurodegenerative diseases. In this work, we employed a multi-disciplinary approach to study the activation mechanism of the CDF protein family. For this we used MamM, one of the main ion transporters of magnetosomes – bacterial organelles that enable magnetotactic bacteria to orientate along geomagnetic fields. Our results reveal that the cytosolic domain of MamM forms a stable dimer that undergoes distinct conformational changes upon divalent cation binding. MamM conformational change is associated with three metal binding sites that were identified and characterized. Altogether, our results provide a novel auto-regulation mode of action model in which the cytosolic domain's conformational changes upon ligand binding allows the priming of the CDF into its transport mode.
EMC Increasing of PWM Rectifier in Comparison with Classical Rectifier
J. Lettl,R. Dolecek
Radioengineering , 2008,
Abstract: Pulse width modulated rectifier is a very popular topic nowadays. The modern industrial production demands continuous and lossless conversion of electrical energy parameters. This need leads to wide spread of power semiconductor converters. The rapid development in power electronics and microprocessor technology enables to apply sophisticated control methods that eliminate negative side effects of the power converters on the supply network. The phase controlled thyristor rectifiers overload the supply network with higher harmonics and reactive power consumption. That is why the PWM rectifier is being examined. In comparison with the phase controlled rectifier it can be controlled to consume nearly sinusoidal current with power factor equal to unity. Another advantage is its capability of energy recuperation. The PWM rectifier can assert itself for its good behavior in many applications, for example as an input rectifier in indirect frequency converter, or in traction. Traction vehicles equipped with PWM rectifier do not consume reactive power, do not load the supply network with higher harmonics, and the recuperation is possible. The paper deals with the PWM rectifier functional model realization and examination. Electromagnetic compatibility of PWM rectifier and classical phase controlled rectifier is compared on the basis of the input current harmonic analysis.
An oxide thermal rectifier  [PDF]
W. Kobayashi,Y. Teraoka,I. Terasaki
Physics , 2009, DOI: 10.1063/1.3253712
Abstract: We have experimentally demonstrated thermal rectification as bulk effect. According to a theoretical design of a thermal rectifier, we have prepared an oxide thermal rectifier made of two cobalt oxides with different thermal conductivities, and have made an experimental system to detect the thermal rectification. The rectifying coefficient of the device is found to be 1.43, which is in good agreement with the numerical calculation.
Temperature Gated Thermal Rectifier  [PDF]
Jia Zhu,Kedar Hippalgaonkar,Sheng Shen,Kevin Wang,Junqiao Wu,Xiaobo Yin,Arun Majumdar,Xiang Zhang
Physics , 2013,
Abstract: Heat flow control is essential for widespread applications of heating, cooling, energy conversion and utilization. Here we demonstrate the first observation of temperature-gated thermal rectification in vanadium dioxide beams, in which an environment temperature actively modulates asymmetric heat flow. In this three terminal device, there are two switchable states, which can be accessed by global heating: Rectifier state and Resistor state. In the Rectifier state, up to 28% thermal rectification is observed. In the Resistor state, the thermal rectification is significantly suppressed (below 4%). This temperature-gated rectifier can have substantial implications ranging from autonomous thermal management of micro/nanoscale devices to thermal energy conversion and storage.
The design of a thermal rectifier  [PDF]
Michel Peyrard
Physics , 2006, DOI: 10.1209/epl/i2006-10223-5
Abstract: The idea that one can build a solid-state device that lets heat flow more easily in one way than in the other, forming a heat valve, is counter-intuitive. However the design of a thermal rectifier can be easily understood from the basic laws of heat conduction. Here we show how it can be done. This analysis exhibits several ideas that could in principle be implemented to design a thermal rectifier, by selecting materials with the proper properties. In order to show the feasibility of the concept, we complete this study by introducing a simple model system that meets the requirements of the design.
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