Press Releases

Entry from: 11.10.2017
Category: News, Press Releases

Making a Super-TARP for Super-activation

Biophysicist Professor Dr. Andrew Plested works at the Leibniz Institute for Molecular Pharmacology in Berlin (Germany). He is hot on the trail of a new mechanism of the synaptic function. Last year, Professor Plested's group was able to demonstrate the super-activation of AMPA receptors. Now, the scientists found the mechanism, involving partner proteins (TARPs). Armed with new insights about TARPs and a newly-generated “super-TARP”, the group will look for super-activation in the brain.

Professor Plested has been chasing AMPA receptors for years. These brain receptors recognize the glutamate released by neighbouring cells. The receptors play a crucial role in the transmission of nerve impulses in the brain. This process is important for such important brain functions as cognition and learning. Last year, biophysicists Andrew Plested and Anna Carbone demonstrated that Stargazin and its relatives can switch this otherwise super-fast receptor to a slow mode with very high activity. This super-activation concept contrasts sharply with prior assumptions, which envisioned that AMPA receptors function only in their fast mode. But nobody knows if super-activation happens in the brain. So far, scientists could only demonstrate super-activation in cell cultures.

Yet another breakthrough discovery paves the way for the FMP team to search for the mechanism in the brain as well. In their newest work*, the team around Andrew Plested describes in detail how interactions between AMPA receptors and their partner proteins modify receptor activities, including generating the characteristic slow currents.
In the brain, AMPA receptors form complexes with their auxiliary subunits such as the TARPs (trans-membrane AMPA receptor regulatory proteins). It was known to scientists that the TARPs and their two major representatives, the Stargazin protein γ2 and protein γ8, regulate the AMPA receptor activity. Until recently, the mechanism of this regulation was unclear. One key missing point was to what extent the action of the partner proteins depends on their ability to form unified complexes with the receptor. In other words, do they associate freely, or with difficulty? A related difficulty was to see how strongly the partners can drive the receptors to change their ways. As in life, meeting is important but how you act is even more. 

Andrew Plested and his team succeeded in separating both these factors and finding the important molecular contacts for super-activation. They discovered this contact area in an unexpected position. The area of contact is located right above the 'collar', which holds the receptor in its closed state. Andrew Plested elaborates: "According to the former consensus among scientists in the field, TARPs were working by rearranging parts of the receptor quite far from the membrane. Nevertheless, our always creative team found a way to discover the real mechanism of action, next to the heart of the channel gate“. 
The team isolated and swapped the extracellular segments of the two partner proteins γ2 and γ8. Using these simple techniques, the scientists then produced entirely passive, so-called “null-TARP” proteins, which meet up easily with AMPARs but do not influence the receptor. On the other hand, they were also able to generate a super-TARP, a variant of the same protein with much more impact on the receptor.

Using the null-TARP and the super-TARP, it should now be feasible to demonstrate the impact of super-activation of AMPA receptors in neurons. "We cannot wait to see what will happen when the partner protein needed for super-activation is muted or super-powered", muses biophysicist Andrew Plested.
Quite possibly, the super-activation may not play any role in the brain, and we are looking at something irrelevant. However, the opposite seems more and more likely. If the super-activation of AMPA receptors is in fact significant in synaptic transmission, it will be a major revision on textbook knowledge. Andrew Plested promises: "If we can establish this molecular mechanism, we could gain new insights into synapse function and brain plasticity. This is particularly exciting because so far, nobody expected slow transmission where AMPA receptors are concerned“.

The paper “Control of AMPA receptor activity by the extracellular loops of auxiliary proteins” already appeared in May in the journal 'bioRxiv', a rapidly expanding archive for pre-release versions of biological science manuscripts. The advantage here was that other scientists could already freely use the information. Recently, the open access journal eLife published the finished version of the article.


Source:
* Riva I†, Eibl CE†, Volkmer R, Carbone AL*, Plested AJR* (2017) Control of AMPA receptor activity by the extracellular loops of auxiliary proteins eLife †these authors contributed jointly. *Corresponding authors

 

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