Featured Research

from universities, journals, and other organizations

Pressure relief valve in cellular membrane identified

Date:
April 16, 2014
Source:
Forschungsverbund Berlin e.V. (FVB)
Summary:
Regulation of cell volume is critical for the body’s cells, for example during cellular exposure to fluids of varying salt concentrations, in cell division and 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.

Regulation of cell volume; schematic diagram.
Credit: FMP/MDC

Regulation of cell volume is critical for the body's cells, for example during cellular exposure to fluids of varying salt concentrations, in cell division and 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 led by Professor Thomas J. Jentsch (Max Delbrόck Center for Molecular Medicine, MDC, Berlin-Buch / Leibniz-Institut fόr Molekulare Pharmakologie, FMP) have now succeeded for the first time in elucidating the molecular identity of this volume-regulated anion channel (VRAC).

Related Articles


The researchers 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.


Story Source:

The above story is based on materials provided by Forschungsverbund Berlin e.V. (FVB). Note: Materials may be edited for content and length.


Journal Reference:

  1. F. K. Voss, F. Ullrich, J. Munch, K. Lazarow, D. Lutter, N. Mah, M. A. Andrade-Navarro, J. P. von Kries, T. Stauber, T. J. Jentsch. Identification of LRRC8 Heteromers as an Essential Component of the Volume-Regulated Anion Channel VRAC. Science, 2014; DOI: 10.1126/science.1252826

Cite This Page:

Forschungsverbund Berlin e.V. (FVB). "Pressure relief valve in cellular membrane identified." ScienceDaily. ScienceDaily, 16 April 2014. <www.sciencedaily.com/releases/2014/04/140416112810.htm>.
Forschungsverbund Berlin e.V. (FVB). (2014, April 16). Pressure relief valve in cellular membrane identified. ScienceDaily. Retrieved December 20, 2014 from www.sciencedaily.com/releases/2014/04/140416112810.htm
Forschungsverbund Berlin e.V. (FVB). "Pressure relief valve in cellular membrane identified." ScienceDaily. www.sciencedaily.com/releases/2014/04/140416112810.htm (accessed December 20, 2014).

Share This


More From ScienceDaily



More Plants & Animals News

Saturday, December 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Researchers Test Colombian Village With High Alzheimer's Rates

Researchers Test Colombian Village With High Alzheimer's Rates

AFP (Dec. 19, 2014) — In Yarumal, a village in N. Colombia, Alzheimer's has ravaged a disproportionately large number of families. A genetic "curse" that may pave the way for research on how to treat the disease that claims a new victim every four seconds. Duration: 02:42 Video provided by AFP
Powered by NewsLook.com
Monarch Butterflies Descend Upon Mexican Forest During Annual Migration

Monarch Butterflies Descend Upon Mexican Forest During Annual Migration

Reuters - Light News Video Online (Dec. 19, 2014) — Millions of monarch butterflies begin to descend onto Mexico as part of their annual migration south. Rough Cut (no reporter narration) Video provided by Reuters
Powered by NewsLook.com
The Best Protein-Filled Foods to Energize You for the New Year

The Best Protein-Filled Foods to Energize You for the New Year

Buzz60 (Dec. 19, 2014) — The new year is coming and nothing will energize you more for 2015 than protein-filled foods. Fitness and nutrition expert John Basedow (@JohnBasedow) gives his favorite high protein foods that will help you build muscle, lose fat and have endless energy. Video provided by Buzz60
Powered by NewsLook.com
Birds Might Be Better Meteorologists Than Us

Birds Might Be Better Meteorologists Than Us

Newsy (Dec. 19, 2014) — A new study suggests a certain type of bird was able to sense a tornado outbreak that moved through the U.S. a day before it hit. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Plants & Animals

Earth & Climate

Fossils & Ruins

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins