The search for the VRAC – three years later
Thomas Jentsch is interested in the function and structure of ion channels. These are small proteins that are present in the membranes of every cell and allow ions such as potassium and chloride to selectively flow into a cell or leave it. Jentsch is considered one of the world's leading researchers his field. Recently, his work was funded with the prestigious Advanced Grant of the European Research Commission for the second time.
In 2014, Jentsch and his team of scientists and the Screening Unit identified the volume-regulating anion channel (VRAC) which has been puzzling scientists for decades.
Professor Jentsch, three years ago you discovered the molecular identity of the anion channel VRAC. Since this breakthrough, what else have you been able to find out about this regulator of cell volume?
Jentsch: The identification of the proteins constituting VRAC is indeed decisive for understanding this important channel which researchers had been studying for more than 30 years. Only knowing its molecular composition one can investigate its localization, details of its molecular working as well as its diverse physiological functions and role in diseases. We have only recently begun to study these aspects, but we have already discovered that VRAC not only regulates the cell volume, but also transports certain neurotransmitters and anti-cancer drugs. Apart from this, we've learned that VRAC consists of five subunits, which can occur in different combinations. For example, the subunit LRRC8D is essential for transport of the chemotherapeutics cisplatin and carboplatin, which are administered to treat various solid tumors.
Are we already involved in clinical research?
Jentsch: Let's put it this way: With the identification of VRAC, we have pushed open the door to many new biological, medical and pharmacological insights. At the moment, we are still operating in the field of basic research, and I never tire of stressing the importance of basic research. The identification of VRAC is a further example of how quickly this flows into concrete medical findings.
Cancer?
Jentsch: Yes, for example. Within one year of the identification of VRAC, we were able to show that chemotherapeutics used to treat cancer pass into the cell through this channel. If the VRAC subunit necessary for this transport is missing, we not only observe a lower degree of tumor cell killing in culture, but also chemotherapy resistance in cancer patients. We demonstrated this in co-operation with a Dutch scientist. Our colleagues analyzed gene expression profiles of ovarian cancer of patients who had been treated with cisplatin or carboplatin. Those who had less of the subunit LRRC8D in their tumors died earlier, in other words were probably partially resistant to this medication.
Had it not been suspected for a long time that VRAC also plays a role in programmed cell death (apoptosis), which chemotherapies are known to activate?
Jentsch: This was a hypothesis that we looked into. Impairment of the cell shrinkage that occurs in apoptosis, so the hypothesis went, reduces the induced cell death of cancer cells. Indeed, cells in which we had genetically eliminated VRAC showed significantly lower levels of programmed cell death. VRAC-related drug resistance of tumors thus may involve a dual mechanism, although we currently assume that the reduced intake of anti-cancer drugs is the more important one.
Are your findings on the transport of neurotransmitters similarly far advanced?
Jentsch: Here, we have been able to confirm the hypothesis that VRAC transports glutamate and other amino acids. A new finding is that this depends on the subunit composition of VRAC and that this channel can also transport GABA. We suspect fascinating roles of specific VRACs in physiological signal transmission in the brain but also, for example, in the development of pathologies like stroke.
Do you already have your sights on a medical target?
Jentsch: In the case of stroke, we know that astrocytes, glial cells found in the central nervous system, swell and release glutamate under hypoxia. This results in glutamate toxicity which in turn results in neuronal cell death. If one could prevent VRAC from releasing glutamate, the damaged brain area would probably be smaller. Using genetic mouse models, we are now investigating this hypothesis in co-operation with a group at the Charité.
What might a therapeutic intervention look like?
Jentsch: It is hoped that drugs may be developed that specifically block those VRACs that allow glutamate to pass, that is channels containing specific combinations of subunits. We are currently searching for substances that modulate the activity of VRAC together with the FMP Screening Unit. But it will no doubt take years to develop new treatment options.
At the beginning of the year, you received your second ERC Advanced Grant. What do you intend to do with the 2.5 million euros?
Jentsch: Well, a part of the project is dedicated to the characterization of VRAC and its physiological and pathological roles, an area in which we expect many new and no doubt in part surprising findings. We have already spoken about some of the aspects involved. The second part aims at the molecular identification of two further important ion channels. These two channels may also lead us into completely new terrain, as was the case with VRAC.
Was VRAC actually the reason for the renewed award?
Jentsch: It wasn't the reason, but an important prerequisite. The identification of VRAC, a central project of my first ERC Advanced Grant, provided not only the basis for the VRAC projects of the second grant, but also demonstrated our ability to carry out such high-risk projects successfully. We will now explore new areas which will hopefully lead to new exciting discoveries.
Thomas J. Jentsch works at the Max Delbrück Center for Molecular Medicine (MDC) and the neighboring Leibniz-Institut für Molekulare Pharmakologie (FMP).
