Dr Anselm Zdebik

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Personal Profile

Name: Anselm Zdebik Email: a.zdebik@ucl.ac.uk
Title: Dr Tel: 0044 20 77940500
Department: Neuro, Physiology & Pharmacology Fax:
Position: Senior Lecturer Address: 1-702 UCL Medical School, Royal Free Campus, Rowland Hill Street, London, NW3 2PF
Research Domain: Basic Life Sciences, Biomedical Imaging (Frontier Disciplines), Experimental Medicine, Neuroscience, Personalised Medicine Web Page: Personal Web Page

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Research Description

CLC proteins have been known as chloride channels for many years and have been implicated in a variety of diseases. KO mice for ClC-2, -3, and ClC-6 have revealed further interesting functions of this protein family. During my postdoctoral fellowship in Thomas Jentsch' laboratory (www.fmp-berlin.de/jentsch.html), I have worked on and generated several CLC-related knock-in mouse models.
After the discovery of chloride/proton antiport in a bacterial CLC homologue, Michael Puschs group (www.ge.cnr.it/ICB/conti_moran_pusch/programs-pusch/home-mik.htm) and ourselves found that ClC-4 and ClC-5 are exchangers rather than chloride channels. Chloride/proton antiport has recently also been shown for lysosomes expressing almost exclusively ClC-7 and its subunit, Ostm1. As revealed by single channel recordings of concatemeric CLC channels and bacterial crystal structures of CLC exchangers, these proteins function as dimers. CLC exchangers can be converted to pure anion conductances by neutralizing a "gating glutamate" conserved in (almost) all CLC proteins. This glutamate will open the chloride pathway when protonated in the wild-type transporter, thereby coupling anion to proton movement.

Research Activities

Chloride/proton exchange function of CLC proteins

KCNJ10/EAST syndrome

Magnetic microbubbles for targeted transfection

TRPV4

Education Description

Physiology at Freiburg, Hamburg, Berlin (Max-Delbruck Centre). Since 2008 Lecturer, Neuroscience, Physiology and Pharmacology, UCL

UCL Collaborators

External Collaborators

Publications

    2014

    • Tondorf F, Ratermann A, Scherl F, Humberg E, Reichold M, Bockenhauer D, Zdebik A, Kleta R, Warth R (2014). Pathophysiology of the p.A167V Mutation of KCNJ10 in mammalian cells. ACTA PHYSIOLOGICA, 210, 146 - 146.
    • Zdebik A, Parrock S, Issler N, Amin-Rasip S, Kleta R, Bockenhauer D (2014). Loss of function through heteromerisation - a novel disease mechanism for EAST syndrome. ACTA PHYSIOLOGICA, 210, 214 - 214.

    2013

    • Zdebik AA, Mahmood F, Stanescu HC, Kleta R, Bockenhauer D, Russell C (2013). Epilepsy in kcnj10 Morphant Zebrafish Assessed with a Novel Method for Long-Term EEG Recordings.. PLoS One, 8(11), e79765 - . doi:10.1371/journal.pone.0079765
    • Parrock S, Hussain S, Issler N, Differ AM, Lench N, Guarino S, Oosterveld MJ, Keijzer-Veen M, Brilstra E, van Wieringen H, Konijnenberg AY, Amin-Rasip S, Dumitriu S, Klootwijk E, Knoers N, Bockenhauer D, Kleta R, Zdebik AA (2013). KCNJ10 Mutations Display Differential Sensitivity to Heteromerisation with KCNJ16.. Nephron Physiol, 123(3-4), 7 - 14. doi:10.1159/000356353
    • Chambrey R, Kurth I, Peti-Peterdi J, Houillier P, Purkerson JM, Leviel F, Hentschke M, Zdebik AA, Schwartz GJ, Hübner CA, Eladari D (2013). Renal intercalated cells are rather energized by a proton than a sodium pump.. Proc Natl Acad Sci U S A, 110(19), 7928 - 7933. doi:10.1073/pnas.1221496110
    • Mahmood F, Mozere M, Zdebik AA, Stanescu HC, Tobin J, Beales PL, Kleta R, Bockenhauer D, Russell C (2013). Generation and validation of a zebrafish model of EAST (epilepsy, ataxia, sensorineural deafness and tubulopathy) syndrome.. Dis Model Mech, 6(3), 652 - 660. doi:10.1242/dmm.009480

    2012

    • Fawcett KA, Murphy SM, Polke JM, Wray S, Burchell VS, Manji H, Quinlivan RM, Zdebik AA, Reilly MM, Houlden H (2012). Comprehensive analysis of the TRPV4 gene in a large series of inherited neuropathies and controls.. J Neurol Neurosurg Psychiatry, 83(12), 1204 - 1209. doi:10.1136/jnnp-2012-303055

    2011

    • Zdebik AA (2011). Beyond ion transport: KCC2 makes cells walk and talk.. J Physiol, 589(Pt 24), 5903 - . doi:10.1113/jphysiol.2011.221754
    • Thompson DA, Feather S, Stanescu HC, Freudenthal B, Zdebik AA, Warth R, Ognjanovic M, Hulton SA, Wassmer E, van't Hoff W, Russell-Eggitt I, Dobbie A, Sheridan E, Kleta R, Bockenhauer D (2011). Altered electroretinograms in patients with KCNJ10 mutations and EAST syndrome.. J Physiol, 589(Pt 7), 1681 - 1689. doi:10.1113/jphysiol.2010.198531
    • Bandulik S, Schmidt K, Bockenhauer D, Zdebik AA, Humberg E, Kleta R, Warth R, Reichold M (2011). The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel.. Pflugers Arch, 461(4), 423 - 435. doi:10.1007/s00424-010-0915-0
    • St Hilaire C, Ziegler SG, Markello TC, Brusco A, Groden C, Gill F, Carlson-Donohoe H, Lederman RJ, Chen MY, Yang D, Siegenthaler MP, Arduino C, Mancini C, Freudenthal B, Stanescu HC, Zdebik AA, Chaganti RK, Nussbaum RL, Kleta R, Gahl WA, Boehm M (2011). NT5E mutations and arterial calcifications.. N Engl J Med, 364(5), 432 - 442. doi:10.1056/NEJMoa0912923
    • Freudenthal B, Kulaveerasingam D, Lingappa L, Shah MA, Brueton L, Wassmer E, Ognjanovic M, Dorison N, Reichold M, Bockenhauer D, Kleta R, Zdebik AA (2011). KCNJ10 mutations disrupt function in patients with EAST syndrome.. Nephron Physiol, 119(3), p40 - p48. doi:10.1159/000330250

    2010

    • Reichold M, Zdebik AA, Lieberer E, Rapedius M, Schmidt K, Bandulik S, Sterner C, Tegtmeier I, Penton D, Baukrowitz T, Hulton SA, Witzgall R, Ben-Zeev B, Howie AJ, Kleta R, Bockenhauer D, Warth R (2010). KCNJ10 gene mutations causing EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy) disrupt channel function.. Proc Natl Acad Sci U S A, 107(32), 14490 - 14495. doi:10.1073/pnas.1003072107
    • Jentsch TJ, Maritzen T, Keating DJ, Zdebik AA, Thévenod F (2010). ClC-3--a granular anion transporter involved in insulin secretion?. Cell Metab, 12(4), 307 - 308. doi:10.1016/j.cmet.2010.08.014
    • Bockenhauer D, Reichold M, Zdebik A, Lieberer E, Schmidt K, Rapedius M, Bandulik S, Sterner C, Tegtmeier I, Baukrowitz T, Hulton SA, Ben-Zeev B, Howie AJ, Warth R, Kleta R (2010). Altered Renal Tubular Ultrastructure and Electrophysiology Caused by KCNJ10 Mutations in EAST Syndrome. PEDIATR NEPHROL, 25(9), 1980 - 1980.
    • Landoure G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ (2010). Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nature Genetics, 42(2), 170 - 174. doi:10.1038/ng.512

    2009

    • Feather SA, Kleta R, Stanescu H, Zdebik A, VanT'Hoff W, Dobbie A, Warth R, Sheridan E, Brockenhauer D (2009). EAST SYNDROME (EPILEPSY, ATAXIA, SENSORINEURAL DEAFNESS AND TUBULOPATHY) IS CAUSED BY MUTATIONS IN KCNJ10. PEDIATR NEPHROL, 24(9), 1793 - 1793.
    • Zdebik AA, Wangemann P, Jentsch TJ (2009). Potassium ion movement in the inner ear: insights from genetic disease and mouse models (vol 24, pg 307, 2009). PHYSIOLOGY, 24(6), 388 - 388. doi:10.1152/physiol.00103.2009
    • Zdebik AA (2009). Statins and fibrate target ClC-1 - from side effects to CLC pharmacology.. Br J Pharmacol, 156(8), 1204 - 1205. doi:10.1111/j.1476-5381.2008.00083.x
    • Bergsdorf EY, Zdebik AA, Jentsch TJ (2009). Residues important for nitrate/proton coupling in plant and mammalian CLC transporters.. J Biol Chem, 284(17), 11184 - 11193. doi:10.1074/jbc.M901170200
    • Bockenhauer D, Feather S, Stanescu HC, Bandulik S, Zdebik AA, Reichold M, Tobin J, Lieberer E, Sterner C, Landoure G, Ruchi A, Sirimanna T, Thompson D, Cross JH, van't Hoff W, Al Masri O, Tullus K, Yeung S, Anikster Y, Klootwijk E, Hubank M, Dillon MJ, Heitzmann D, Arcos-Burgos M, Knepper MA, Dobbie A, Gahl WA, Warth R, Sheridan E, Kleta R (2009). Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations. New England Journal of Medicine, 360(19), 1960 - 1970.
    • Zdebik AA, Wangemann P, Jentsch TJ (2009). Potassium ion movement in the inner ear: insights from genetic disease and mouse models.. Physiology (Bethesda), 24, 307 - 316. doi:10.1152/physiol.00018.2009

    2008

    • Zdebik AA, Zifarelli G, Bergsdorf EY, Soliani P, Scheel O, Jentsch TJ, Pusch M (2008). Determinants of anion-proton coupling in mammalian endosomal CLC proteins. Journal of Biological Chemistry, 283(7), 4219 - 4227. doi:10.1074/jbc.M708368200
    • Rickheit G, Maier H, Strenzke N, Andreescu CE, De Zeeuw CI, Muenscher A, Zdebik AA, Jentsch TJ (2008). Endocochlear potential depends on Cl- channels: mechanism underlying deafness in Bartter syndrome IV.. EMBO J, 27(21), 2907 - 2917. doi:10.1038/emboj.2008.203

    2007

    • Jentsch J, Zdebik A, Fuhrmann J (2007). Cell biology of the CIC-5 chloride transporter in nephrolithiasis (Dent's disease). PEDIATR NEPHROL, 22(9), 1418 - 1418.

    2006

    • Poet M, Kornak U, Schweizer M, Zdebik AA, Scheel O, Hoelter S, Wurst W, Schmitt A, Fuhrmann JC, Planells-Cases R, Mole SE, Hubner CA, Jentsch TJ (2006). Lysosomal storage disease upon disruption of the neuronal chloride transport protein CIC-6. P NATL ACAD SCI USA, 103(37), 13854 - 13859. doi:10.1073/pnas.06061347103

    2004

    • Zdebik AA, Cuffe JE, Bertog M, Korbmacher C, Jentsch TJ (2004). Additional disruption of the ClC-2 Cl(-) channel does not exacerbate the cystic fibrosis phenotype of cystic fibrosis transmembrane conductance regulator mouse models.. Journal of Biological Chemistry, 279(21), 22276 - 22283. doi:10.1074/jbc.M309899200

    2003

    • Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2003). Molecular structure and physiological function of chloride channels (vol 82, pg 503, 2002). PHYSIOL REV, 83(2), 1A - 1A.
    • Renstrom E, Gutcher I, Jing X, Maritzen T, Salehi A, Zdebik A, Lundquist I, Jentsch T, Rorsman P (2003). Defective insulin release machinery and insulin granule acidification in chloride channel 3null (ClC3(-/-)) mice.

    1997

    • Zdebik A, Hug MJ, Greger R (1997). Chloride channels in the luminal membrane of rat pancreatic acini.. Pflugers Arch, 434(2), 188 - 194.

    1996

    • Zdebik A, Hug MJ, Greger R (1996). Low concentrations of carbachol induce oscillations of membrane voltage towards E(Cl-) but not the Nernst potential for nonselective cation channels in rat pancreatic acinar cells. CELL PHYSIOL BIOCHEM, 6(1-2), 123 - 128.
    • Slawik M, Zdebik A, Hug MJ, Kerstan D, Leipziger J, Greger R (1996). Whole-cell conductive properties of rat pancreatic acini.. Pflugers Arch, 432(1), 112 - 120.