Press Releases

Entry from: 27.02.2019
Category: News, Press Releases

Pharmacological master key discovered to calm nerve activity

A research team from Berlin and Kiel discovers new pharmacological mechanism in potassium channels. With this, excessive electrical activity in nerve or muscle cells can be contained. The results have been published in the renowned scientific journal Science.

Schematic illustration of a potassium channel showing the binding site of the experimental pharmaceuticals (shown here as a key) at the so-called selectivity filter (binding site of the K+ ions). The coloured arrows symbolize the multitude of natural mechanisms that open the selectivity filter in cells. © Physiologisches Institut, CAU Kiel

Electrical signals form the basis of many life processes - they allow the heart to beat and we can think, see, hear, taste, smell or touch. Excessive electrical activity of nerve cells or muscle cells, however, can also be harmful, leading to epilepsy, cardiac arrhythmias, hypertension, migraine, and other painful conditions.

Electrical signals are generated by the targeted opening and closing of ion channels. These are pores in the cell membrane through which electrically charged particles (such as sodium ions and potassium ions) are transported. It is therefore not surprising that many drugs act on ion channels, and that in particular drugs that reduce excessive electrical activity are of great pharmacological interest. The research focus is on a special class of ion channels, the so-called potassium channels. There are about 80 different members of potassium channels in the human body and many of them have the task of suppressing excess electrical activity in nerve cells and muscle cells.
Without this electrical suppression, cells would die from over-excitement.  Scientists at the Physiological Institute of the Medical Faculty of the Christian-Albrechts-University Kiel (CAU) and at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) have now discovered a novel mechanism that acts as a master key to open certain ion channels simultaneously and thereby suppress excessive activity in cells.

Dr. Han Sun (FMP) used molecular dynamics simulations in combination with X-ray crystallographic and functional mutagenesis data to determine where the negatively charged activators bind in the channels. "Interestingly, the negatively charged group of activators is just below the selectivity filter, where it interacts with potassium ions under the filter," says Dr. Sun. With the help of extensive computational simulations, which were partially carried out at the Norddeutschen Verbund für Hoch- und Höchstleistungsrechnen (HLRN) (North German Association for High Performance Computing), the ion flow through the selectivity filter was able to be simulated. From this analysis, researchers were able to decipher the mechanism by which negatively charged activators open the channels and accelerate the ion flux. "Surprisingly, this mechanism is universally valid for a number of important neuroprotective ion channels and could constitute a starting point for rational drug discovery," adds Dr. Sun.
The Kiel working group "Ion Channels" headed by Professor Thomas Baukrowitz investigated the molecular biophysics of ion channels, i.e. those processes that lead to the opening and closing of ion channels in the cell. "Potassium channels are so interesting to us because they are versatile in their regulation: they can be opened by voltage, temperature or mechanical stress - but also by the use of certain substances," explains Prof. Baukrowitz. Such substances are in a test phase and are not yet approved for trials or the pharmaceutical market. In their publication with international participation, the Kiel researchers discovered that a number of long-known substances do not work as originally thought, specifically on a certain type of potassium channels, but rather open many different potassium channels simultaneously. This so-called polypharmacology was previously unknown for potassium channels. Some of the substances used in this work were synthesized in the group of Dr. Marc Nazaré at FMP.
„Similar to a master key, the substances open different potassium channels simultaneously with the valve mechanism," says Dr. Schewe from Kiel. Prof. Baukrowitz adds: „To some extent, these compounds alienated the natural function of the channel pore to open it up. The fact that this valve mechanism works in very similar ways in different types of potassium channels was not known. Our study provides a better understanding of how potassium channels work.“ The obtained knowledge from this study could, for example, help pharmaceutical companies to develop more efficient new medicines, especially those used to treat diseases such as epilepsy, arrhythmias, vasoconstriction, or various types of pain.


Source:

Schewe M*, Sun H*, Mert Ü, Mackenzie A, Pike ACW, Schulz F, Constantin C, Vowinkel KS, Conrad LJ, Kiper AK, Gonzalez W, Musinszki M, Tegtmeier M, Pryde DC, Belabed H, Nazare M, de Groot BL, Decher N, Fakler B, Carpenter EP, Tucker SJ, Baukrowitz T., A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels., Science. 2019 Feb 22;363(6429):875-880. doi: 10.1126/science.aav0569.

* These authors contributed equally to this work

Kontakt:
Dr. Han Sun
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
hsun(at)fmp-berlin.de
Tel.: 49 (0) 309 406 2902
leibniz-fmp.de/sun.html


Öffentlichkeitsarbeit
Silke Oßwald
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Tel.: +49 (0) 309 479 3104
Email: osswald(at)fmp-berlin.de
 
Das Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) gehört zum Forschungsverbund Berlin e.V. (FVB), einem Zusammenschluss von acht natur-, lebens- und umweltwissenschaftlichen Instituten in Berlin. In ihnen arbeiten mehr als 1.900 Mitarbeiter. Die vielfach ausgezeichneten Einrichtungen sind Mitglieder der Leibniz-Gemeinschaft. Entstanden ist der Forschungsverbund 1992 in einer einzigartigen historischen Situation aus der ehemaligen Akademie der Wissenschaften der DDR.