DOCSLIB.ORG

Vracs Swallow Platinum Drugs

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Vracs Swallow Platinum Drugs News & Views VRACs swallow platinum drugs Thomas Voets, Bernd Nilius & Rudi Vennekens Platinum-based drugs such as cisplatin react covalently with the N7 nitrogen in essential structural component of VRACs and carboplatin are on the WHO model list guanines (Galluzzi et al, 2012). This causes (Qiu et al, 2014; Voss et al, 2014). LRRC8 of essential medicines, as highly effective distortions in the DNA, which can provoke proteins form a small family of integral chemotherapeutic drugs for the treatment cell cycle arrest and ultimately programmed membrane proteins with four transmem- of various solid tumors. These drugs react cell death (Kelland, 2007; Galluzzi et al, brane helices and include five homologues with purine residues in DNA, thereby caus- 2012). However, before cisplatin and related (LRRC8A-E) in mammals and most other ing DNA damage, inhibition of cell division, drugs can exert their antiproliferative effects, chordates (Abascal & Zardoya, 2012). and eventually cell death. However, the they first need to be taken up by the targeted Current evidence indicates that functional mechanisms whereby platinum-based cells (Galluzzi et al, 2012). Cisplatin and VRAC channels are heteromultimers that drugs enter cancer cells remained poorly carboplatin are relatively polar, compared to contain the obligatory LRRC8A subunit understood. In this issue, Planells-Cases other classes of small-molecule (anticancer) supplemented with at least one of the other et al (2015) provide evidence that cells drugs. Consequently, their passive diffusion four isoforms (Voss et al, 2014). Based on take up cisplatin and carboplatin via through the plasma membrane is slow, and limited homology with pannexins, a hexam- volume-regulated anion channels (VRACs), other transport pathways, including trans- eric architecture has been proposed, but this more specifically VRACs composed of porters and channels, have been postulated. stoichiometry still demands experimental LRRC8A and LRRC8D subunits. In particular, the copper transporter CTR1 verification (Abascal & Zardoya, 2012). has been proposed to mediate cisplatin In a genomewide screen for genes that See also: R Planells-Cases et al uptake (Ishida et al, 2002), although this mediate cisplatin and carboplatin resistance, has been disputed (Ivy & Kaplan, 2013). Planells-Cases et al (2015) discovered that ifty years ago, while testing the effect Planells-Cases et al (2015) now propose that gene-inactivating insertions in the LRRC8A of electrical fields on the growth of VRACs act as entry channels for cisplatin and LRRC8D genes resulted in significantly F bacteria, researchers discovered that and carboplatin. VRACs are ubiquitous increased survival of cancer cells when metal complexes of platinum released from channels that typically open in response to grown in the presence of the two platinum- the electrodes had a strong inhibitory effect cell swelling or any other maneuver that based drugs. Moreover, cells deficient in on bacterial cell division (Rosenberg et al, dilutes the cellular ionic content (Nilius either LRRC8A or LRRC8D exhibited 1965). This serendipitous discovery fueled et al, 1997; Pedersen et al, 2015). VRACs strongly reduced cellular platinum levels, further successful research into the anti- are best known for their key role in the suggesting that resistance to cisplatin and proliferative effects of different platinum- homeostasis of cell volume, but they have carboplatin is due to impaired cellular containing molecules in mammalian cancer also been implicated in cellular processes uptake of these drugs rather than to effects cells. By the end of the 1970s, a first including regulation of the membrane poten- on downstream processes. Interestingly, platinum-based drug, cisplatin (Fig 1A), was tial, release of transmitter and cell prolifera- hypotonic cell swelling caused a striking approved for the treatment of testicular and tion (Nilius et al, 1997). increase in cisplatin/carboplatin uptake. ovarian cancers. Currently, cisplatin and Earlier work had already suggested a Overall, the results support the idea that the second- and third-generation platinum-based functional role for VRACs in cisplatin- platinum-based drugs can permeate VRACs drugs such as carboplatin and oxaliplatin induced cell death. However, since the composed of LRRC8A and LRRC8D subunits. are amongst the most widely used and effec- molecular nature of the functionally well- It may seem dubious to assume that the tive anticancer drugs (Kelland, 2007). characterized VRACs had remained elusive pore of an anion-selective channel could In the last decades, the biochemical for decades (Pedersen et al, 2015), the exact accommodate a large, non-charged, plat- mechanisms whereby cisplatin and related role of these channels in platinum drug- inum complex. Since cisplatin and oxali- compounds inhibit cell proliferation have induced effects remained murky. Recently, platin do not carry charge, it is technically been largely unraveled. Briefly, once inside the chloride channel field breathed a sigh of impossible to directly measure their flux cells, platinum-based drugs undergo aqua- relief when two groups independently iden- through VRACs using electrophysiological tion (i.e. the incorporation of water mole- tified leucine-rich repeat-containing protein techniques. Nevertheless, earlier work has cules) and enter the nucleus where they 8A (LRRC8A; also dubbed SWELL1) as an provided ample indications that VRACs may Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium. E-mail: [email protected] DOI 10.15252/embj.201593357 ª 2015 The Authors The EMBO Journal 1 The EMBO Journal Platinum-based drugs enter via VRACs Thomas Voets et al LRRC8D-containing VRACs, irrespective of Cl – cell volume changes, which could then be Cisplatin Cisplatin used to increase the effectiveness of plat- Cl NH Carboplatin inum-based drugs. Some caution is required Pt 3 NH VRACs here, as several earlier studies have linked Cl 3 VRAC activity to cell cycle progression, and Taurine pharmacological agents that inhibit VRACs O Cell were generally found to act as potent inhi- membrane S bitors of cell proliferation (Voets et al, HO NH2 O 1995; Shen et al, 2000; Pedersen et al, Cytosol 2015). Therefore, pharmacological upregu- Carboplatin Cl – Cl – lation of VRAC function in vivo may have O NH unwanted stimulatory effects on cell O 3 Pt growth. It is also known that various CELL DEATH O NH3 widely used drugs, including for instance O the anti-estrogen tamoxifen and the antide- 12–14Å pressant fluoxetine (Prozac), potently inhibit VRACs (Pedersen et al, 2015) and VRAC pore may thus potentially influence the uptake LRRC8B,C,E LRRC8A LRRC8D of platinum drugs by cancer cells in patients. Finally, knowledge about the entry mechanisms of platinum-based drugs might also be exploited to prevent their entry into Figure 1. Permeability of VRACs for platinum-based drugs. non-cancer cells. For instance, one of the Left: structure and dimension of platinum-based drugs in comparison with chloride ions and the VRAC- most common and burdensome side effects permeant osmolyte taurine. Right: VRACs are composed of the obligatory LRRC8A subunit complemented with of platinum-based drugs is the development additional LRRC8B-E subunits. VRACs containing LRRC8D exhibit high permeability for the platinum-based anticancer drugs cisplatin and carboplatin, allowing drug entry into cells to cause cell death. The hexameric of neuropathic pain, which is due to an stoichiometry of VRACs is an educated guess based on limited homology with pannexin/connexin channels. effect of the drugs on peripheral nerves and the surround tissue (Avan et al, 2015). Peripheral inhibition of LRRC8D-containing be permeable to larger (and not necessarily LRRC8D is about 40 amino acids longer than VRACs might be a strategy to prevent these negatively charged) molecules, including in the other isoforms (Abascal & Zardoya, adverse effects. amino acids, sugars, ATP, and the sulfonic 2012). It is therefore tempting to speculate acid taurine, and estimates of the diameter that this first extracellular domain of LRRC8 References of the VRAC pore are in the range of proteins forms a reentrant pore loop in Abascal F, Zardoya R (2012) LRRC8 proteins 12–14 A˚ (Pedersen et al, 2015). As such, the VRACs and that the extended loop in share a common ancestor with pannexins, molecular dimensions of cisplatin and carbo- LRRC8D results in an enlarged pore that and may form hexameric channels involved platin would be at least compatible with facilitates permeation of platinum-based in cell-cell communication. BioEssays 34: pore permeation (Fig 1). Planells-Cases et al drugs and organic osmolytes. 551 – 560 (2015) provide evidence that permeability to In addition to providing important Avan A, Postma TJ, Ceresa C, Cavaletti G, such larger molecules is dependent on the insights into the VRAC pore, the new Giovannetti E, Peters GJ (2015) Platinum- subunit composition of VRACs, in that chan- results may have significant clinical impact. induced neurotoxicity and preventive nels containing the LRRC8D subunit conduct Reduced cellular uptake is one key mecha- strategies: past, present, and future. Oncologist more cisplatin and taurine (Fig 1). This nism, whereby cancer cells can become 20: 411 – 432 suggests that LRRC8D differs from the other resistant to platinum-based drugs (Galluzzi Galluzzi L, Senovilla L, Vitale I, Michels J, Martins I, LRRC8 isoforms in
Load more

Recommended publications
  • LRRC8A Regulates Hypotonicity-Induced NLRP3 Inflammasome Activation
    bioRxiv preprint doi: https://doi.org/10.1101/2020.06.11.146225; this version posted June 12, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. LRRC8A regulates hypotonicity-induced NLRP3 inflammasome activation Jack P. Green1*,#, Tessa Swanton1*, Lucy V. Morris1, Lina Y. El-Sharkawy2, James Cook1, Shi Yu1, James Beswick2, Antony Adamson3, Neil Humphreys3,4, Richard A. Bryce2, Sally Freeman2, Catherine Lawrence1,5, David Brough1,5,# 1Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, AV Hill Building, Oxford Road, Manchester, M13 9PT, UK. 2Division of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. 3Genome Editing Unit Core Facility, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK. 4Present address: EMBL-Rome, Epigenetics and Neurobiology Unit, Adriano Buzzati- Traverso Campus, Via Ramarini 32, 00015 Monterotondo (RM), Italy. 5Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester M13 9PT, UK. * Contributed equally # To whom correspondence should be addressed: David Brough. Tel: +44 (0)161 275 5039; Email: [email protected] Jack Green. Tel +44 (0)161 306 0502; Email: [email protected] 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.06.11.146225; this version posted June 12, 2020.
    [Show full text]
  • Abstracts Genome 10K & Genome Science 29 Aug - 1 Sept 2017 Norwich Research Park, Norwich, Uk
    Genome 10K c ABSTRACTS GENOME 10K & GENOME SCIENCE 29 AUG - 1 SEPT 2017 NORWICH RESEARCH PARK, NORWICH, UK Genome 10K c 48 KEYNOTE SPEAKERS ............................................................................................................................... 1 Dr Adam Phillippy: Towards the gapless assembly of complete vertebrate genomes .................... 1 Prof Kathy Belov: Saving the Tasmanian devil from extinction ......................................................... 1 Prof Peter Holland: Homeobox genes and animal evolution: from duplication to divergence ........ 2 Dr Hilary Burton: Genomics in healthcare: the challenges of complexity .......................................... 2 INVITED SPEAKERS ................................................................................................................................. 3 Vertebrate Genomics ........................................................................................................................... 3 Alex Cagan: Comparative genomics of animal domestication .......................................................... 3 Plant Genomics .................................................................................................................................... 4 Ksenia Krasileva: Evolution of plant Immune receptors ..................................................................... 4 Andrea Harper: Using Associative Transcriptomics to predict tolerance to ash dieback disease in European ash trees ............................................................................................................
    [Show full text]
  • The LRRC8A:C Heteromeric Channel Is a Cgamp Transporter and the Dominant
    bioRxiv preprint doi: https://doi.org/10.1101/2020.02.13.948273; this version posted February 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells Lauren J. Lahey1,2, Xianlan Wen3, Rachel E. Mardjuki2,4, Volker Böhnert2,5, Christopher Ritchie2,5, Jacqueline A. Carozza2,4, Gaelen T. Hess2,6, Merritt Maduke3, Michael C. Bassik2,6, and Lingyin Li2,5,7,* 1Biophysics Program, 2Stanford ChEM-H, 3Department of Molecular and Cellular Physiology, 4Department of Chemistry, 5Department of Biochemistry, 6Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305 USA. 7Lead Contact *Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.02.13.948273; this version posted February 14, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SUMMARY Extracellular 2'3'-cyclic-GMP-AMP (cGAMP) is an immunotransmitter secreted by cancer cells and taken up by host cells to activate the anti-cancer STING pathway. No cGAMP exporter has been identified, and SLC19A1, a recently identified cGAMP importer, does not account for the import actiVity in most cell types. Here, we identify the LRRC8A:C heteromeric channel, a volume-regulated anion channel (VRAC), as a cGAMP transporter. This channel mediates cGAMP import or export depending on the cGAMP chemical gradient. cGAMP influences anion influx through VRAC, indicating it is likely a direct substrate of the channel.
    [Show full text]
  • Selective Transport of Neurotransmitters and Modulators by Distinct Volume-Regulated LRRC8 Anion Channels Darius Lutter1,2,3, Florian Ullrich1,2, Jennifer C
    © 2017. Published by The Company of Biologists Ltd | Journal of Cell Science (2017) 130, 1122-1133 doi:10.1242/jcs.196253 RESEARCH ARTICLE Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels Darius Lutter1,2,3, Florian Ullrich1,2, Jennifer C. Lueck1,2,3, Stefan Kempa2 and Thomas J. Jentsch1,2,4,* ABSTRACT volume regulation (Jentsch, 2016; Nilius et al., 1997; Pedersen In response to swelling, mammalian cells release chloride and et al., 2016). This plasma membrane channel, which appears to be organic osmolytes through volume-regulated anion channels expressed in all cells, is normally closed but can be activated by cell swelling or other cellular signaling cascades. In most cells, VRAC (VRACs). VRACs are heteromers of LRRC8A and other LRRC8 − isoforms (LRRC8B to LRRC8E), which are co-expressed in HEK293 opening leads to an efflux of Cl , which, together with an efflux of + + and most other cells. The spectrum of VRAC substrates and its K through independent K channels, lowers the intracellular dependence on particular LRRC8 isoforms remains largely unknown. osmolarity and, by secondarily driving water efflux, results in We show that, besides the osmolytes taurine and myo-inositol, regulatory volume decrease. Cell swelling also stimulates an efflux ‘ ’ myo LRRC8 channels transport the neurotransmitters glutamate, of organic osmolytes such as -inositol, taurine and glutamate. aspartate and γ-aminobutyric acid (GABA) and the co-activator It was controversial whether this release occurs through VRAC or D-serine. HEK293 cells engineered to express defined subsets of through a distinct channel named VSOAC (for volume-sensitive LRRC8 isoforms were used to elucidate the subunit-dependence organic osmolyte/anion channel) (Jackson and Strange, 1993; of transport.
    [Show full text]
  • The LRRC8A:C Heteromeric Channel Is a Cgamp Transporter and the Dominant Cgamp Importer in Human Vasculature Cells
    bioRxiv preprint doi: https://doi.org/10.1101/2020.02.13.948273; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells Lauren J. Lahey1,2, Xianlan Wen3, Rachel E. Mardjuki2,4, Volker Böhnert2,5, Gaelen T. Hess2,6, Christopher Ritchie2,5, Jacqueline A. Carozza2,4, Merritt Maduke3, Michael C. Bassik2,6, and Lingyin Li2,5,7,* 1Biophysics Program, 2Stanford ChEM-H, 3Department of Molecular and Cellular Physiology, 4Department of Chemistry, 5Department of Biochemistry, 6Department of Genetics, Stanford University, School of Medicine, Stanford, CA 94305 USA. 7Lead Contact *Correspondence: [email protected] bioRxiv preprint doi: https://doi.org/10.1101/2020.02.13.948273; this version posted March 27, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. SUMMARY Extracellular 2'3'-cyclic-GMP-AMP (cGAMP) is an immunotransmitter secreted by cancer cells and taken up by host cells to activate the anti-cancer STING pathway. No cGAMP exporter has been identified, and SLC19A1, a recently identified cGAMP importer, does not account for the import actiVity in most cell types. Here, we identify the LRRC8A:C heteromeric channel, a volume-regulated anion channel (VRAC), as a cGAMP transporter. This channel mediates cGAMP import or export depending on the cGAMP chemical gradient, and channel activation or inhibition modulates cGAMP transport.
    [Show full text]
  • Analysis of the Indacaterol-Regulated Transcriptome in Human Airway
    Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2018/04/13/jpet.118.249292.DC1 1521-0103/366/1/220–236$35.00 https://doi.org/10.1124/jpet.118.249292 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 366:220–236, July 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Analysis of the Indacaterol-Regulated Transcriptome in Human Airway Epithelial Cells Implicates Gene Expression Changes in the s Adverse and Therapeutic Effects of b2-Adrenoceptor Agonists Dong Yan, Omar Hamed, Taruna Joshi,1 Mahmoud M. Mostafa, Kyla C. Jamieson, Radhika Joshi, Robert Newton, and Mark A. Giembycz Departments of Physiology and Pharmacology (D.Y., O.H., T.J., K.C.J., R.J., M.A.G.) and Cell Biology and Anatomy (M.M.M., R.N.), Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada Received March 22, 2018; accepted April 11, 2018 Downloaded from ABSTRACT The contribution of gene expression changes to the adverse and activity, and positive regulation of neutrophil chemotaxis. The therapeutic effects of b2-adrenoceptor agonists in asthma was general enriched GO term extracellular space was also associ- investigated using human airway epithelial cells as a therapeu- ated with indacaterol-induced genes, and many of those, in- tically relevant target. Operational model-fitting established that cluding CRISPLD2, DMBT1, GAS1, and SOCS3, have putative jpet.aspetjournals.org the long-acting b2-adrenoceptor agonists (LABA) indacaterol, anti-inflammatory, antibacterial, and/or antiviral activity. Numer- salmeterol, formoterol, and picumeterol were full agonists on ous indacaterol-regulated genes were also induced or repressed BEAS-2B cells transfected with a cAMP-response element in BEAS-2B cells and human primary bronchial epithelial cells by reporter but differed in efficacy (indacaterol $ formoterol .
    [Show full text]
  • The Conserved DNMT1-Dependent Methylation Regions in Human Cells
    Freeman et al. Epigenetics & Chromatin (2020) 13:17 https://doi.org/10.1186/s13072-020-00338-8 Epigenetics & Chromatin RESEARCH Open Access The conserved DNMT1-dependent methylation regions in human cells are vulnerable to neurotoxicant rotenone exposure Dana M. Freeman1 , Dan Lou1, Yanqiang Li1, Suzanne N. Martos1 and Zhibin Wang1,2,3* Abstract Background: Allele-specifc DNA methylation (ASM) describes genomic loci that maintain CpG methylation at only one inherited allele rather than having coordinated methylation across both alleles. The most prominent of these regions are germline ASMs (gASMs) that control the expression of imprinted genes in a parent of origin-dependent manner and are associated with disease. However, our recent report reveals numerous ASMs at non-imprinted genes. These non-germline ASMs are dependent on DNA methyltransferase 1 (DNMT1) and strikingly show the feature of random, switchable monoallelic methylation patterns in the mouse genome. The signifcance of these ASMs to human health has not been explored. Due to their shared allelicity with gASMs, herein, we propose that non-tradi- tional ASMs are sensitive to exposures in association with human disease. Results: We frst explore their conservancy in the human genome. Our data show that our putative non-germline ASMs were in conserved regions of the human genome and located adjacent to genes vital for neuronal develop- ment and maturation. We next tested the hypothesized vulnerability of these regions by exposing human embryonic kidney cell HEK293 with the neurotoxicant rotenone for 24 h. Indeed,14 genes adjacent to our identifed regions were diferentially expressed from RNA-sequencing. We analyzed the base-resolution methylation patterns of the predicted non-germline ASMs at two neurological genes, HCN2 and NEFM, with potential to increase the risk of neurodegenera- tion.
    [Show full text]
  • Regulated Anion Channel Is Altered in Glaucoma
    www.nature.com/scientificreports OPEN The LRRC8-mediated volume- regulated anion channel is altered in glaucoma Received: 11 December 2017 Xavier Gasull 1,2,3, Marta Castany4, Aida Castellanos1,2,3, Mikel Rezola1,2,3, Alba Andrés-Bilbé1,2,3, Accepted: 4 March 2019 Maria Isabel Canut5, Raúl Estévez6, Teresa Borrás7 & Núria Comes 1,2,3 Published: xx xx xxxx Regulation of cellular volume is an essential process to balance volume changes during cell proliferation and migration or when intracellular osmolality increases due to transepithelial transport. We previously characterized the key role of volume-regulated anion channels (VRAC) in the modulation of the volume of trabecular meshwork (TM) cells and, in turn, the aqueous humour (AH) outfow from the eye. The balance between the secretion and the drainage of AH determines the intraocular pressure (IOP) that is the major casual risk factor for glaucoma. Glaucoma is an ocular disease that causes irreversible blindness due to the degeneration of retinal ganglion cells. The recent identifcation of Leucine-Rich Repeat-Containing 8 (LRRC8A-E) proteins as the molecular components of VRAC opens the feld to elucidate their function in the physiology of TM and glaucoma. Human TM cells derived from non- glaucomatous donors and from open-angle glaucoma patients were used to determine the expression and the functional activity of LRRC8-mediated channels. Expression levels of LRRC8A-E subunits were decreased in HTM glaucomatous cells compared to normotensive HTM cells. Consequently, the activity of VRAC currents and volume regulation of TM cells were signifcantly afected. Impaired cell volume regulation will likely contribute to altered aqueous outfow and intraocular pressure.
    [Show full text]
  • Comparative Transcriptome Profiling of Selected Osmotic Regulatory Proteins in the Gill During Seawater Acclimation of Chum Salm
    www.nature.com/scientificreports OPEN Comparative transcriptome profling of selected osmotic regulatory proteins in the gill during seawater acclimation of chum salmon (Oncorhynchus keta) fry Sang Yoon Lee 1, Hwa Jin Lee2 & Yi Kyung Kim1,2* Salmonid fshes, chum salmon (Oncorhynchus keta) have the developed adaptive strategy to withstand wide salinity changes from the early life stage. This study investigated gene expression patterns of cell membrane proteins in the gill of chum salmon fry on the transcriptome level by tracking the salinity acclimation of the fsh in changing environments ranging from freshwater (0 ppt) to brackish water (17.5 ppt) to seawater (35 ppt). Using GO analysis of DEGs, the known osmoregulatory genes and their functional groups such as ion transport, transmembrane transporter activity and metal ion binding were identifed. The expression patterns of membrane protein genes, including pump-mediated protein (NKA, CFTR), carrier-mediated protein (NKCC, NHE3) and channel-mediated protein (AQP) were similar to those of other salmonid fshes in the smolt or adult stages. Based on the protein-protein interaction analysis between transmembrane proteins and other related genes, we identifed osmotic-related genes expressed with salinity changes and analyzed their expression patterns. The fndings of this study may facilitate the disentangling of the genetic basis of chum salmon and better able an understanding of the osmophysiology of the species. Salinity is one of the critical factors limiting the distribution patterns of all aquatic organisms1–4. Salmonid fshes display diverse life-history traits; anadromous individuals that mature in the river from hatching through to juveniles acquire the capacity to tolerate salinity associated with parr–smolt transformation and undergo ocean migrations before returning to rivers for spawning, whereas landlocked types spend their entire life within fresh- water5,6.
    [Show full text]
  • Cryo-EM Structure of the Volume-Regulated Anion Channel
    bioRxiv preprint doi: https://doi.org/10.1101/331207; this version posted May 25, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Cryo-EM structure of the volume-regulated anion channel LRRC8 Go Kasuya1*, Takanori Nakane1†*, Takeshi Yokoyama2*, Yanyan Jia3, Masato Inoue4, Kengo Watanabe4, Ryoki Nakamura1, Tomohiro Nishizawa1, Tsukasa Kusakizako1, Akihisa Tsutsumi5, Haruaki Yanagisawa5, Naoshi Dohmae6, Motoyuki Hattori7, Hidenori Ichijo4, Zhiqiang Yan3, Masahide Kikkawa5, Mikako Shirouzu2, Ryuichiro Ishitani1, Osamu Nureki1‡ 1Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 2-11-16 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan; 2Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama-shi, Kanagawa 230-0045, Japan; 3State Key Laboratory of Medical Neurobiology, Ministry of Education Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China; 4Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; 5Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; 6RIKEN, Global Research Cluster, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan; 7State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 2005 Songhu Road, Yangpu District, Shanghai 200438, China.
    [Show full text]
  • Leucine-Rich Repeat Containing 8A Contributes to the Expansion Of
    © 2020. Published by The Company of Biologists Ltd | Biology Open (2020) 9, bio048264. doi:10.1242/bio.048264 RESEARCH ARTICLE Leucine-rich repeat containing 8A contributes to the expansion of brain ventricles in zebrafish embryos Yen-Tzu Tseng1, Chun-Lin Ko1, Chia-Teng Chang1, Yen-Hua Lee1, Wei-Chun Huang Fu2 and I-Hsuan Liu1,3,4,* ABSTRACT outwardly rectifying Cl− current and consequently an RVD when The sodium osmotic gradient is necessary for the initiation of brain cells were exposed to hypotonic solutions (Cahalan and Lewis, 1988; ventricle inflation, but a previous study predicted that organic and Hazama and Okada, 1988). Later, organic osmolytes such as inorganic osmolytes play equivalently important roles in osmotic taurine were considered accountable for at least half of the total homeostasis in astrocytes. To test whether organic osmoregulation RVD, and hence a putative volume-sensitive organic osmolyte/anion also plays a role in brain ventricle inflation, the core component for channel (VSOAC) was proposed for this activity (Garcia-Romeu volume-regulated anion and organic osmolyte channel, lrrc8a,was et al., 1991; Jackson and Strange, 1993; Strange and Jackson, 1995). investigated in the zebrafish model. RT-PCR and whole-mount in situ Due to the pharmacological similarity and controversial experimental hybridization indicated that both genes were ubiquitously expressed results, the question of whether VRAC is identical to VSOAC was through to 12 hpf, and around the ventricular layer of neural tubes and once a highly debated issue (Díaz et al., 1993; Kirk and Kirk, 1994; the cardiogenic region at 24 hpf. Knocking down either one lrrc8a Lambert and Hoffmann, 1994; Sanchez-Olea et al., 1995; Shennan paralog with morpholino oligos resulted in abnormalities in circulation et al., 1994).
    [Show full text]
  • (A) Sample Contribution to the PLS Model
    SUPPLEMENTARY DATA Supplementary Figure 1. Correlation of levels of auto-antibodies with disease duration. (A) Sample contribution to the PLS model. The bars represent the distances of individual samples to the PLS model, which represent the contribution of individual samples to the separation between T1DM and T2DM/NGT captured by the PLS model. A small distance indicates high contribution of the corresponding sample to the separation captured by the PLS model. The numbers in parenthesis in the x- axis labels of T1DM samples represent the disease durations in months. (B) Scatterplot of disease duration and sample contribution to the separation between T1DM and T2DM/NGT captured by the PLS model (i.e. distances of samples to the PLS model). The distances showed no significant correlation (r = –0.465 and P = 0.070) with disease durations of the individual samples. ©2014 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1566/-/DC1 SUPPLEMENTARY DATA Supplementary Figure 2. Expression of EEF1A1 and UBE2L3 in human tissues. Immunohistochemistry of tissue array showed that (A) EEF1A1 and (B) UBE2L3 were expressed in skin, liver, kidney, stomach, intestine, lung, adrenal gland, and thyroid gland as well as pancreas. Original magnification 400. 헑 ©2014 American Diabetes Association. Published online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-1566/-/DC1 SUPPLEMENTARY DATA Supplementary Figure 3. Detection of EEF1A1 and UBE2L3 auto-antibodies by immunoblotting. Three pairs of T1DM patient samples were selected from the second cohort based on their ELISA absorbance values categorized in three groups: high: >1.3, medium: <1.3 and >0.5, and low: <0.5 absorbance at 450 nm (A450nm).
    [Show full text]