Rapid reaction thanks to "precision protein"


Whether we are driving our car or playing football – in many situations, we have to react to external stimuli in the blink of an eye. But how is it achieved that signal transmission between the nerve cells of our body takes place in fractions of a second? Scientists at the Freie Universität Berlin, the Charité University Medicine Berlin and the Leibniz-Institut für Molekulare Pharmakologie, collaborating in an international research association, have now made an important contribution to elucidating this mechanism. They discovered that a certain protein (Unc13A) provides for an extremely precise molecular "link" at the connecting points of nerve cells – synapses – and is thus responsible for ultra-rapid transmission of the stimuli. The results, which have now been published in the journal "Nature Neuroscience", give insights into the principles by which synapses optimise signal transmission spatially and temporally and with high precision on a molecular level. 

Vesikel = Vesicle; Kalzium-Konzentration = Calcium concentration; niedrig = low; hoch = high. Illustration of neurotransmitter release via Unc13A and Unc13B. Unc13A is positioned at a distance of 70 nm from the calcium source (Cac; blue) by Bruchpilot (BRP; green) and RBP (red). Unc13B (orange) is positioned at a greater distance of 120 nm. The colour transition from dark to light blue in the background indicates different levels of calcium concentration, which are detected by vesicles. Illustration: Alexander Walter, FMP.


Nerve cells communicate with the aid of electrical and chemical signals. Transmission of the stimuli from cell to cell takes place at special connecting points, the synapses. There, the incoming electrical signal is transformed into a chemical signal which is  transported over the very narrow synaptic cleft, which separates two adjacent cells from each other, in order then to be converted back into an electrical signal which is then propagated further. The chemical stimulus conduction takes place via chemical messenger substances, so-called neurotransmitters, which are located in small vesicles in the synapse. If an electrical impulse arrives at the synapse, it changes the electrical potential of the cell membrane which leads to the opening of calcium channels, causing calcium ions to briefly flow into the synapse.

In turn, the increase in calcium concentration leads to the fusion of vesicles with the plasma membrane releasing their neurotransmitter content into the synaptic cleft, which then diffuses to and activates the postsynaptic cell leading for example to the contraction of a muscle. All this takes place within a few milliseconds, which is only possible, among other things, because the distance between vesicles and the calcium channels in the cell membrane is precisely defined. Just how precisely this mechanism is regulated has now been determined by scientists from the NeuroCure Cluster of Excellence led by Prof. Dr. Stephan Sigrist and Dr. Alexander Walter of the Leibniz-Institut für Molekulare Pharmakologie using the motoneuronal nervous system of the fruit fly (Drosophila melanogaster). They discovered that the protein Unc13A connects the neurotransmitter-filled vesicle with nanometer precision to the calcium source – i.e. the calcium channels in the cell membrane –and thus enables lightning-fast and efficient signal transmission.

Two further proteins that play a role in the exact positioning of Unc13A and thus the vesicles have now been identified with the help of the research groups led by Prof. Dr. Ulrich Stelzl from the University of Graz and Prof. Dr. Markus Wahl from the Freie Universität Berlin: Like two callipers on a ruler, these two proteins ensure that the well-defined distance between vesicle and the calcium source is always maintained. A surprising aspect for the scientists was that the very closely related protein Unc13B plays a subordinate role in signal transmission. The reason for this – as suggested by the experiments and theoretical calculations – is probably because the protein is not connected so closely to the calcium source (as Unc13A). Unc13B is also held in place in the network of another protein complex, but at a larger distance. The differences in length fluctuate only on a nanometer scale (1 nanometer = 1 millionth of a millimetre), and could only be detected with a particularly high resolution microscope in the laboratory of Chemistry Nobel Prize winner Prof. Dr. Stefan Hell  from the Max Planck Institute for Biophysical Chemistry in Göttingen.

Nevertheless, the scientists are convinced that this leads to completely different functionalities: While Unc13A enables a rapid and efficient signal conduction, Unc13B barely plays a role here, due to its minimally greater distance from the calcium source. However, the researchers also provide evidence that it is rather required in the development of the synapse. The researchers' work has put them on the track of a very important, but mechanistically so far poorly understood principle: how synapses regulate their transmission properties through spatial control of the vesicle position.

Original publication:
Mathias A Böhme, Christina Beis,  Suneel Reddy-Alla,  Eric Reynolds, Malou M Mampell, Andreas T Grasskamp, Janine Lützkendorf, Dominique Dufour Bergeron,  Jan H Driller, Husam Babikir, Fabian Göttfert, Iain M Robinson, Cahir J O'Kane, Stefan W Hell, Markus C Wahl, Ulrich Stelzl, Bernhard Loll, Alexander M Walter & Stephan J Sigrist Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca2+ channel-vesicle coupling. Nat Neurosci. 2016 Aug 15. Link zum Artikel
Press Release of the Leibniz-Institut für molekulare Pharmakologie (FMP)
Dr. Alexander M. Walter
Molecular and Theoretical Neuroscience
Leibniz Institute für Moleculare Pharmakologie
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