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

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

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, VRAC volume-regulated anion channels, and the recently identified acid-activated anion channel ASOR. 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 and that VRAC enhances innate immunity by transporting the messenger molecule cGAMP. Recently (2019) we have identified still another chloride channel, ASOR. 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 >)

ACID-ACTIVATED CHLORIDE CHANNEL. ASOR is a chloride channel that appears to be ubiquitously expressed in vertebrate cells and that needs acidic extracellular pH for activation. ASOR is important  under pathological conditions, but its physiological roles remain enigmatic although its wide expression pattern suggests that it is very important.  Although identified in electrophysiological studies more than 10 years ago, the proteins constituting this channel has remained unknown. Using a genome-wide siRNA screen with a sophisticated functional read-out, we recently identified TMEM206 proteins as constituting this channel. TMEM206 has two transmembrane domains, both of which appear to line the ion-selective pore as determined by mutagenesis. All tested vertebrate orthologs, including those from lizard or acid-insensitive naked mole rats, display a strong pH-dependence. Our molecular identification of TMEM206/ASOR channels finally open the door to investigate the biological function of this enigmatic, but apparently important chloride channel.

Ullrich et al., eLife (2019).     Research Highlight

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 and second messengers such as cGAMP. This suggests 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.

Most recently, in a collaboration with Prof. Xiao, we found that VRAC also transports the important messenger molecule cGAMP (cyclicGAMP-AMP). cGAMP is produced by an enzyme called cGAS that is activated by double stranded DNA in the cytoplasm. DNA is present in the cytoplasm e.g. after infection with DNA viruses, or, due to genomic instability, in cancer. cGAMP, after binding to an intracellular receptor called STING, activates the transcription of interferon and thereby stimulates the innate immune response. We showed that cGAMP is transported by VRACs across plasma membranes and thereby can reach non-infected bystander cells in the vicinity, where it enhances the production of interferon. Indeed, KO mice for a VRAC subunit that is particularly important for cGAMP transport showed less interferon response and higher viral titers than WT mice. Hence, VRAC importantly boosts the immune response to DNA viruses.

Neurotransmitter transport by VRAC: Lutter et al., JCS 2017.
VRAC in insulin secretion: Stuhlmann et al., Nature comm. 2018.
VRAC in cGAMP transport and immune response: Zhu et al., Immunity 2020.  Research Highlight

Our current research on VRACs focuses on structure-function, its regulation, and in particular on its roles in physiology and pathology. It is now one of 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 inJ 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 (Weinert et al., Novarino et al.; Science 2010)..

More recently, we extended these findings to ClC-3  (Weinert et al., EMBO J 2020). Whereas disruption of ClC-3 leads to  neurodegeneration (complete loss of the hippocampus), its conversion to a chloride conductor in Clcn3unc/unc mice surprisingly did not lead pathology. However, this can be explained by compensation by ClC-4, with which ClC-3 forms heterodimers. The loss of ClC-3, but not its conversion to ClC-3unc, markedly  lowered ClC-4 protein levels largely abolishing compenstaion by ClC-4 in the KO, but not in KI mice. Hence, probably all vesicular CLCs depend on Cl-/H+ exchange activity for their bilogical function.

We recently discovered a new human channelopathy caused by mutations  in  CLCN6 (Polovitskaya et al., AJHG 2020). Whereas disruption of ClC-6 in mice leads to mild neuronal storage, a recurrent missense mutation that enhances ClC-6 currents and leads to a loss of it pH-dependence leads to very severe developmental delay and neurodegeneration. This point mutant leads to grossly enlarged lysosome-like vesciles in tranfected cells, an effcet that is abolished by converting ClC-6 into an uncoupled chloride conductor.   Research Highlight

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).

To prove that the opening of ClC-2 entails hyperaldosteronism, we generated a knock-in mouse model expressing a ClC-2 variant that carries a deletion in the N-terminal gating region. This deletion opens ClC-2 to the same degree as the human mutations we and others had identified in human patients. Patch-clamp analysis of adrenal glomerulosa cells showed that they were strongly depolarized by the dramatically larger chloride conductance. This resulted in increased aldosterone synthase transcription, high serum aldosterone, reduced serum renin, and arterial hypertension. These mice constitute the best mouse model for human aldosteronism to date. (see  Göppner et al, Nature Comm. 2019).

We recently investigated cellular effects of ClC-2 disruption in additional mouse models, and continue to analyze the various disease-related roles of ClC-2 in more detail.


Research Highlight 1       Research Highlight 2       Research Highlight 3       Research Highlight 4     Research Highlight 5   Research Highlight 6   Research Highlight 7   Research Highlight 8  
Research Highlight 9     Research Highlight 10  Research Highlight 11

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)

Diese Website verwendet Cookies zur Verbesserung des inhaltlichen Angebots. Datenschutz OK