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

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

Prof.  Thomas J. Jentsch
Phone: +49-30-9406-2961    Fax:  +49-30-9406-2960
jentsch(at)fmp-berlin.de

Research Lab Coordinator  Dr. Norma Nitschke
Phone: +49-30-9406-2974     Fax: +49-30-9406-2960
nitschke(at)fmp-berlin.de

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

CV for download

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, thick bones (osteopetrosis), and primary hyperaldosteronism, among others. Our work bridges the gap between molecular studies and systems biology.

Our research focuses currently on CLC chloride channels and transporter, and VRAC volume-regulated anion channels. At the same time, we explore several new directions. In 2014, we have established the long-sought molecular identity of VRAC, which is ubiquitously expressed in mammalian cells. VRAC not only plays a central role in cell volume regulation, but also in amino-acid and neurotransmitter release. VRAC is believed to be important in several physiological and pathological conditions. We have already shown that VRAC plays a role in tumor drug resistance and in insulin secretion by pancreatic β-cells. To focus on these new areas, we have closed our long-standing, very successful research programs on KCNQ potassium channels, KCC K-Cl-cotransporters, and TMEM16 (Anoctamin) Ca-activated chloride channels.

 

(more >)

VOLUME-REGULATED ANION CHANNELS (VRACs).  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-Cas9. 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. We extended the latter finding by structure-function analysis.  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 by 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

In addition to inorganic anions, drugs, and taurine, VRAC also transports many neurotransmitters. This sugegsts a role in extracellular signal transduction, in particular in the nervous system. To explore the physiological functions of VRAC, we have generated several KO mice. In addition, we are generating  KI mice in which the addition of epitopes to individual LRRC8 subunits allows their detection by immunohistochemistry in mouse tissues. We showed that insulin-secreting pancreatic β-cells markedly express LRRC8D. Using mice in which we disrupted the essential VRAC subunit Lrrc8a specifically in β-cells, we demonstrated that VRAC modulates insulin secretion. Glucose uptake by β-cells increases cytoplasmic osmolarity. The ensuing cell swelling opens VRAC, leading to depolarization, opening of voltage-dependent Ca-channels, and increased insulin secretion. Hence VRAC also plays a role in intracellular signaling.

Neurotransmitter transport by VRAC: Lutter et al., JCS 2017.
VRAC in insulin secretion: Stuhlmann et al., Nature comm. 2018.

Our current research on VRACs focuses on structure-function, its regulation, and in particular on its roles in physiology and pathology. It is now our main area of research.

CLC CHLORIDE CHANNELS AND TRANSPORTERS. Back in 1990, we achieved a major breakthrough by molecularly identifying the first voltage-gated Cl channel, which we isolated from the Torpedo electric organ and subsequently named ClC-0. It defined the CLC gene family, which in mammals comprises nine members. These proteins function either as plasma membrane Cl channels or as intracellular (vesicular) 2Cl/H exchangers. Our lab investigated all CLC proteins in considerable detail and discovered several important pathologies in mice and humans that are due to mutations in their genes. (Recent reviews in J Physiol and Physiol. Rev. )

In the CLC area, our research is currently focusing on the role of vesicular CLCs in endosomal/lysosomal function and ion homeostasis, and on ClC-2 in various pathologies, in particular its recently discovered role in primary hyperaldosteronism.

Vesicular CLC proteins may help in the luminal acidification of endosomes and lysosomes. 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. (Weinert et al., Novarino et al.). Our current research on vesicular CLCs focuses on their role in luminal ion homeostasis and the impact on vesicular trafficking.

Disruption of the widely expressed plasma membrane Cl channel ClC-2 leads to various pathologies in mice and humans, including blindness, male infertility, and leukodystrophy. Surprisingly, our French collaborators very recently discovered a ClC-2 mutation in a patient with primary hyperaldosteronism, which is associated with high blood pressure. Together we analyzed the effect of this mutation, which affects a residue in a gating region we had identified back in 1992 (Gründer et al, Nature), in cell culture and frog oocytes. The mutation strongly increases ClC-2 currents, leading to a depolarizing Cl efflux in aldosterone-producing glomerulosa cells in the adrenal cortex. This depolarization leads to an increase in transcription of the enzyme aldosterone synthase (see Fernandes-Rosa et al., Nature Genet. 2018). We are currently investigating this and other ClC-2 related phenotypes using mouse models.

 

 

 

The Other Jentsch

 

 

Leibniz-Forschungsinstitut 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)
info(at)fmp-berlin.de

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