Department Physiology and Pathology of Ion Transport (Thomas J. Jentsch)

Our group belongs both to the MDC and the FMP and is located in the new  Timoféeff-Ressovsky-Haus on the campus Berlin-Buch in Berlin.

Prof.  Thomas J. Jentsch
Phone: +49-30-9406-2961    Fax:  +49-30-9406-2960

Research Lab Coordinator  Dr. Norma Nitschke
Phone: +49-30-9406-2974     Fax: +49-30-9406-2960

Prof.  Thomas J. Jentsch

1982 Ph.D. (physics) Freie Universität Berlin and Fritz-Haber-Institut der Max-Planck-Gesellschaft.
1984 M.D. Freie Universität Berlin
Doctoral and postdoctoral work at the Institut für Klinische Physiologie, Freie Universität Berlin
Postdoctoral work with Harvey Lodish at the Whitehead Institute for Biomedical Research (MIT)  1986-1988
Research Group Leader at the ZMNH, Hamburg University  1988 - 1993
Full professor and Director of the Institute for Molecular Neuropathology at the ZMNH  1993-2006
Director of the ZMNH, 1995-1998, 2001-2003
2006- Full professor at the Charité Berlin, Head of research group Physiology and Pathology of Ion Transport at the FMP (Leibniz-Institut für Molekulare Pharmakologie) and MDC (Max-Delbrück-Centrum für Molekulare Medizin)
2008- Principal Investigator of Neurocure



The Journal of Physiology celebrates the discovery of CLC channels and transporters by Thomas Jentsch 25 years ago with a special issue.

Research overview >

Ion transport processes play crucial roles in neuronal excitability, signal transduction, transport of salt, water, and other substances across epithelia, and the homeostasis of extracellular, cytosolic, and vesicular compartments.

Our highly interdisciplinary investigations stretch from structure-function studies and biophysics to cell biological aspects like endocytosis and to the physiological and systemic role of particular transport proteins. We have identified several human diseases that are due to mutations in ion channels and have generated various knock-out mouse models. Their phenotypes yield important insights into the normal role of particular ion transporters and indicate candidate genes for human diseases. In accord with the broad importance of ion transport, these disorders include epilepsy and neurodegeneration, deafness, kidney stones, urinary protein loss, hypertension, and thick bones (osteopetrosis), among others. Our work bridges the gap between molecular studies and systems biology.

We investigate the functions of CLC chloride channels and transporter, KCNQ potassium channels, KCC K-Cl-cotransporters, and Anoctamin Ca-activated chloride channels. We have recently identified the long-sought molecular identity of VRAC, the volume-regulated anion channel that is ubiquitously expressed in mammalian cells. VRAC not only plays a central role in cell volume regulation, but also in amino-acid release and is believed to be important in several pathological conditions.

(more >)

IDENTIFICATION OF THE LONG-SOUGHT VOLUME-ACTIVATED ANION CHANNEL VRAC.  Cells need to regulate their volume when exposed to osmotic stress and during processes like cell division, growth, and apoptosis. A key player in regulatory volume decrease is the ubiquitously expressed volume-activated anion channel VRAC which has been studied extensively over the past three decades. However, attempts to identify the underlying molecules have failed repeatedly. We now performed an unbiased genome-wide RNA interference screen using a functional read-out and identified the membrane protein LRRC8A as essential subunit of VRAC. However, LRRC8A needs heteromerization with other members of this gene family to reconstitute VRAC currents in cells in which LRRC8A,B,C,D,E have all been deleted using CRISPR-Cas. Combinations of different LRRC8 isoforms yield currents with different inactivation kinetics, explaining the differences in VRAC properties observed in vivo. Furthermore, we showed that VRAC conducts also organic osmolytes like taurine. Our work finally provides the basis for investigating the structure-function relationship of this important channel, to elucidate the mechanism by which cell swelling leads to VRAC opening, and to examine the role of VRAC in various pathologies. Our initial identification and characterization of VRAC has been published in Science (2014).

Voss et al., Science 2014   Suppl. Info   News and Views

More recently, we showed that the substrate specificity of VRAC depends on its subunit composition, demonstrating that LRRC8 heteromers form its pore. LRRC8D increased the selectivity for the organic osmolyte taurine and for the important cancer drug cisplatin,. We showed that VRAC plays a dual role in cisplatin sensitivity be mediating its uptake and by promoting apoptosis. Downregulation of LRRC8D may be clinically important in tumor drug resistance.

Planells-Cases et al., EMBO J. 2015    Expanded View  Suppl. Information  News and Views



BACK TO CLASSICS.  In the classical picture of vesicular acidification, electrical currents of the H+-ATPase are neutralized by a Cl- channel (left). However, we have shown that endosomal CLC proteins, instead of being Cl- channels, are rather Cl-/H+ exchangers (centre), raising the question what this exchange is good for. In our most recent work, we generated knock-in mice in which we converted selected CLC exchangers into channels using single point mutations (right panel). These mice should display normal acidification of endosomes (for ClC-5) or lysosomes (for ClC-7). Surprisingly, both mouse models (Clcn5unc and Clcn7unc, unc for uncoupled from protons) display phenotypes (impaired endocytosis or neurodegeneration) that largely overlap with those of the respective KOs. We suggest that there is an important, previously unrecognized role of luminal chloride concentration. These exciting results, which have profound implications for cell biology of endolysosomal trafficking and function, have been published 2010 in Science.          See Weinert et al. and Novarino et al.

The Other Jentsch



Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)