Press Releases

Entry from: 16.07.2019
Category: News, Press Releases

FMP Researchers Identify "Gearbox" in Glutamate Receptor

Glutamate receptors play an important role in the communication of brain cells. How they function in detail isn’t fully clear. A team of researchers led by Professor Andrew Plested, scientist at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), has now discovered that the ion selectivity filter of a glutamate receptor is central to its function. This new and surprising finding might be significant for treatment of brain dysfunctions, such as epilepsy.

Many research groups are investigating glutamate receptors because they are the key to rapid communication in the brain: as transmembrane proteins in neurons, they control synaptic transmission in nerve cells. Andrew Plested, head of the FMP research group, Molecular Neuroscience and Biophysics, has also been researching ionotropic glutamate receptors for 20 years. Ionotropic glutamate receptors include an ion channel; if the neurotransmitter glutamate binds to the receptor, the channel opens. This is a central event in neurotransmission. These glutamate receptors consist of an extracellular part and a region within the membrane (transmembrane domain, TMD). "Previously, little research had been devoted to the membrane part of the receptor because it is more difficult to investigate than is the area outside of the cell," said Andrew Plested.

To find out more, the FMP researchers, with the team consisting of Mette Poulsen, Anahita Poshtiban, Viktoria Klippenstein and Valentina Ghisi focused on the TMD of AMPA receptors, which of the three different ionotropic glutamate receptor types are the type that found most widely in the nervous system. For their analysis, the FMP researchers employed a method that had only rarely been used for glutamate receptors: They used chemically synthesized amino acids that react with protein segments in their environment when exposed to UV light. This allowed the team to get at the part of the receptor located inside the membrane. "We examined the TMD at a total of 30 different points. At each site, we put the light-sensitive amino acids and then irradiated the receptors with UV light. This restricted the movement of the receptor around the site we had targeted, and we looked at how the receptor reacted. This approach allowed us for the first time to examine almost every part of the TMD," reports Andrew Plested.

The results surprised him and his team since they contradicted the prevailing assumption that the extracellular part, in particular, is most crucial for controlling the receptor. There is a selectivity filter in the TMD, through which certain substances, primarily potassium and sodium ions, enter the cell interior. Previously, it had been assumed that this filter functioned like a gate that was always open. Perhaps substances could pass at some times and could not pass at other times; but how this filter was controlled was unclear. "We were able to show that the selectivity filter works in a complex manner and is not static as had been previously assumed, but on the contrary it is a central, dynamic part, linked to other parts of the receptor," summarizes Plested. In addition, for the first time he and his team described precisely how a "cuff" located at the top of the TMD works. Together the cuff and the filter form a sort of gearbox of the AMPA receptor that controls the conductivity and activity of the receptor.

With their work, the FMP team was able to decipher hitherto unknown details of the function of glutamate receptors. "We now have a much more accurate picture of how such receptors work," says Plested. The new findings might be used to better understand and manipulate processes in the brain, for example by means of new therapeutics that either attenuate or amplify the response of the receptor. Such approaches are interesting for treatment of functional disorders of the brain, such as epilepsy. Recently, it was shown that blocking certain AMPA receptors in the forebrain can target epilepsy. Specific approaches are desirable, since in the brain stem, AMPA receptors are required for example for controlling respiration.

The path to the new findings was unexpectedly long. It was almost four years before Andrew Plested and his team were able to generate the data that opened up a new door: "We had to use new analytical methods and techniques because initially we did not find anything that we could use. However, then once we established the cuff and filter as key moving parts in the TMD, we could develop totally new insights, which was a great reward for the entire team," reports the FMP researcher.

The results show that the selectivity filter works in a manner that is very complex and coupled to many other processes in the receptor. In subsequent research activities Andrew Plested will investigate the nature of this coupling and how to interfere with it.


Source:
Poulsen MH, Poshtiban A, Klippenstein V, Ghisi V, Plested AJR. (2019) Gating modules of the AMPA receptor pore domain revealed by unnatural amino acid mutagenesis. Proc Natl Acad Sci U S A. 2019 Jul 2;116 (27):13358-13367. doi: 10.1073/pnas.1818845116. Epub 2019 Jun 18.

Contact:

Prof. Dr. Andrew Plested
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
E-Mail: plested@fmp-berlin.de
Phone.: +49 (0)30 94793-245
Lab website: www.leibniz-fmp.de/plested

Public Relations
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Silke Oßwald
Phone: +49 (0)30 94793 104
Email: osswald(at)fmp-berlin.de
 
The Leibniz-Institut für Molekulare Pharmakologie (FMP) is part of the Forschungsverbund Berlin e.V. (FVB), who legally represents eight non-university research institutes - members of the Leibniz Association - in Berlin. The institutions pursue common interests within the framework of a single legal entity while maintaining their scientific autonomy. More than 1,900 employees work within the research association. The eight institutes were founded in 1992 and emerged from former institutes of the GDR Academy of Sciences.



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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