Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Pressure Relief Valve in Cellular Membrane Identified

16.04.2014

Regulation of cell volume is critical for the body’s cells, f. e. during cellular exposure to fluids of varying salt concentrations, in cell division, cell growth, but also in diseases such as cancer, stroke and myocardial infarction.

A certain chloride channel, a membrane protein that allows the passage of the chloride ion, is of crucial importance in volume regulation. It is activated by the swelling of the cell and then releases chloride ions and organic matter (osmolytes) from the cell. Researchers in Berlin-Buch have now succeeded for the first time in elucidating the molecular identity of this volume-regulated anion channel (VRAC) (Science Express, DOI: 10.1126/science.1252826)*.


The volume-regulated anion channel VRAC

(Scheme: Lab. Jentsch/Copyright: MDC/FMP)

Researchers led by Professor Thomas J. Jentsch (Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch/Leibniz-Institut für Molekulare Pharmakologie, FMP) identified a molecule, LRRC8A, which is an essential constituent of the volume-regulated anion channel (VRAC). This protein needs to be assembled with related proteins (LRRC8B to E) to form channels with probably six subunits.

They could also show for the first time that these chloride channels are also permeable to small organic molecules such as taurine or amino acids. For over 20 years, research groups across the globe have been seeking to elucidate the molecular structure of the volume-regulated anion channel (VRAC). It took Jentsch’s team almost four years to achieve this breakthrough.

The regulation of cell volume is important for many functions in the organism. The volume-regulated anion channel (VRAC) which Thomas Jentsch and his coworkers Felizia Voss and Tobias Stauber now identified at the molecular level is expressed in all vertebrate cells.

If a particular cell volume is exceeded, the channel opens and permits the outflow of osmolytes such as chloride ions as well as small organic molecules such as taurine and amino acids. By contrast, cations such as potassium or sodium cannot permeate.

Once the channel is opened, chloride and other osmolytes pass in a passive process called diffusion. Due to its biophysical properties the channel only allows anions and certain organic compounds to pass. Thus, the cell reduces the concentration of its osmolytically active constituents to (or even below) that of the surrounding fluid. At the same time, the water content of the cell decreases as the water molecules flow out via aquaporins in the cell membrane. The volume of the cell decreases again.

LRRC8A was discovered as a VRAC component using a genome-wide RNA interference (siRNA) screen in collaboration with Katina Lazarow and Jens von Kries from the FMP Screening Unit. By means of short RNA snippets, the translation of the genetic information into the corresponding proteins can be suppressed. Using a one-by-one approach in a large-scale cell culture experiment, the Berlin group transiently silenced the products of all approximately 20,000 human genes.

In an automated screening process the researchers investigated which of the genes are required for the swelling-activated anion flux across the cell membrane. The approximately 130,000 time-dependent ion flux measurements were statistically analyzed with help from the Bioinformatics Group of the MDC (Nancy Mah/Miguel Andrade-Navarro).

The essential role of LRRC8 proteins in the volume-regulated anion channel was verified using CRISPR/Cas technology, which just became available during the past two years. With this method, specific genes on the chromosomes can be disrupted completely. Different combinations of LRRC8 proteins, all including the obligate LRRC8A, – either by omitting some of the family members from gene disruption or by reconstituting different combinations – led to different electrophysiological properties of the channel. “This allows us to explain the behavior of the channel in different tissues which until now had remained elusive,” Thomas Jentsch said.

"Cells can swell or in the worst case even burst. Water transport and content must therefore be tightly regulated," he added. Water transport is always driven by the osmotic gradient. Cells take up chloride from their surroundings, whereas organic substances such as taurine or amino acids are produced within the cells.

Deciphering the molecular structure of this chloride channel may also pave the way for better medical treatments, for example, after stroke. "In the case of damage in the brain, cells swell and release glutamate, which acts upon receptors on nerve cells. The subsequent inflow of calcium raises the intracellular concentration of this ion to toxic levels," Jentsch said. With the onset of programmed cell death (apoptosis) during cancer chemotherapy, however, there is a strong reduction in cell volume. The volume-regulated chloride channel also appears to be involved in this process.

*Identification of LRRC8 Heteromers as Essential Component of the Volume-regulated Anion Channel VRAC.

Felizia K. Voss1,2,3, Florian Ullrich1,2,3, Jonas Münch1,2,3, Katina Lazarow1, Darius Lutter1,2,3, Nancy Mah2, Miguel A. Andrade-Navarro2, Jens P. von Kries1, Tobias Stauber1,2 * and Thomas J. Jentsch1,2,4 *
*Correspondence to: Jentsch@fmp-berlin.de (T.J.J.); tstauber@fmp-berlin.de (T.S.).

1Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin
2Max Delbrück Center for Molecular Medicine (MDC), Berlin
3Graduate program of the Freie Universität Berlin
4Neurocure, Charité Universitätsmedizin, Berlin
Science Express, 10. April 2014; DOI: 10.1126/science.1252826

Contact:
Barbara Bachtler
Press Department
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Robert-Rössle-Straße 10
13125 Berlin
Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
e-mail: presse@mdc-berlin.de
http://www.mdc-berlin.de/

Silke Oßwald
Public Relations
Leibniz-Institut für Molekulare Pharmakologie
im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
Phone: +49-30-94793-104
e-mail: osswald@fmp-berlin.de
http://www.fmp-berlin.info/de/home.html

The Max Delbrück Center for Molecular Medicine (MDC) is one of 18 research centers of the Helmholtz Association. It was founded in 1992 to link basic molecular basic research with clinical research. The MDC is working closely with the Charité - University Medicine in the Berlin Institute of Health (BIH) and has evolved in recent years into an internationally recognized research institute.

The Leibniz-Institut für Molekulare Pharmakologie (FMP) is part of the Forschungsverbund Berlin e.V. (FVB), a federation of eight institutes in Berlin in the field of natural, life and environmental sciences with a staff of more than 1500 employees. The multiple award-winning institutions are members of the Leibniz Association. The Forschungsverbund came into being in 1992 in a unique historical situation as the successor organization of the former Academy of Sciences of the GDR.

Barbara Bachtler | Max-Delbrück-Centrum

Further reports about: Cellular FMP Leibniz-Institut MDC Medicine Molecular Relief Valve acids amino chloride genes proteins volume

More articles from Life Sciences:

nachricht Repairing damaged hearts with self-healing heart cells
22.08.2017 | National University Health System

nachricht Biochemical 'fingerprints' reveal diabetes progression
22.08.2017 | Umea University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

Cholesterol-lowering drugs may fight infectious disease

22.08.2017 | Health and Medicine

Meter-sized single-crystal graphene growth becomes possible

22.08.2017 | Materials Sciences

Repairing damaged hearts with self-healing heart cells

22.08.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>