Research Highlights

Entry from: 22.02.2017
Category: Research Highlights

New insights into the nerve cell: What really happens when a vesicle fuses with the cell membrane

NEURON They are not visible to the naked eye, and yet so many different things depend on them: the vesicles in our synapses. Much research has been done into the fact that these tiny bubbles secrete messenger substances and, in the process, fuse with the cell membrane, after which they are recycled by the nerve cell. But how quickly and in what way all of this takes place has been the matter of heated debate for some time. Now, researchers from the Leibniz-Institut für Molekulare Pharmakologie (FMP) in Berlin have for the first time shown that the uptake of the vesicle membrane and the production of new vesicles are two largely independent mechanisms. The surprising finding is that the nerve cell has borrowed the uptake mechanism in part from baker's yeast. With the publication of their work in the high-ranking journal "Neuron", the researchers have now not only settled a long-standing scientific debate, but also provided the neurosciences with important impulses for the future.

Electron micrographs of synapses from stimulated hippocampal neurons that were mock-treated (left) or treated with the formin inhibitor SMIFH2 (right): Note the accumulation of tubular plasma membrane extensions (yellow arrows) and the depletion of endosome-like vacuoles (asterisks) in the formin inhibitor treated synapse.

Vesicles in nerve cell synapses have an important function: The tiny bubbles contain chemical messenger substances, so-called neurotransmitters, which are needed to conduct electrical signals from one nerve cell to the next. Similar vesicles are responsible for the release of hormones such as insulin in other tissues. The importance of neurotransmission is witnessed by the fact that the 2013 Nobel Prize for Medicine was awarded for research on vesicle formation and fusion.

It is known that the synaptic vesicles fuse with the cell membrane upon secretion of the messenger substances and that the nerve cell subsequently takes up the vesicle membrane again, in order to recycle it into a new vesicle. But the question of how quickly all this happens and how this process, called endocytosis, takes place mechanistically, has escalated into a full-blown conflict between scientists. However, none of the existing theories could answer the question of how it is possible that the process takes place so smoothly, given that different nerve cells fire electrical impulses at different speeds.

Two work steps are the solution to the puzzle

Researchers from the Leibniz-Institut für Molekulare Pharmakologie (FMP) have now found an answer. Experiments with low-frequency nerve cells of the hippocampus and the calyx synapses of the auditory brain stem, which fire around 100 times more rapidly, have shown: The uptake of the vesicle membrane and the production of new vesicles are two largely independent mechanisms. This form of work division explains among other things why slow-firing nerve cells can take up more "material" than they can supply as "goods".

"Nerve cells apparently have the ability to take in large amounts of vesicle membrane in the shortest of time," says the Director of the Institute and project leader Prof. Dr. Volker Haucke, "while the process of producing new vesicles in the correct size, condition and quality takes place thereafter." By keeping a reserve supply, the nerve cell has all the time in the world to make a proper vesicle again, he continues. That is important in order to restore the tension of the plasma membrane, which is lost as a result of the fusion process, yet, needed to maintain the excitability of the nerve cell. "We have now understood for the first time how different types of nerve cells manage to remain excitable under different stimulation conditions," explains Dr. Tolga Soykan, the first author of the study.

The researchers themselves were surprised by the fact that the uptake mechanism concerned is of ancient evolutionary origin, namely being related to the endocytosis known from baker's yeast. The mechanism, dependent on linear filaments of the protein actin, is apparently simple, so that at first sight it does not seem to fit in with the complicated process of vesicle production. And yet this unequal pair makes sense. Depending on the stimulus, the membrane uptake mechanism in nerve cells can be very rapid: from a few seconds in the case of high-frequency activity to less than a second in the case of a stimulation of the nerve cell by single electrical impulses. In this way, the uptake mechanism keeps the clathrin scaffold protein, which requires almost a minute to reform a new vesicle, free to carry out its complicated task. For a long time, it was thought that the scaffold protein, which is similar in structure to a football-shaped honeycomb, is necessary together with its partner proteins for the uptake of the vesicle membrane. As the Berlin scientists have now shown, the clathrin scaffold is indeed immensely important, but it is not necessary for the first step of membrane endocytosis: "Clathrin does not come into effect until the first step, the actual endocytosis, is complete," explains Haucke. " Because vesicle reformation needs to be precise and, thus, is so much more complicated, it also works much more slowly than the actin-based membrane uptake mechanism taken over in part from baker's yeast."

Finding from Berlin creates new research principles

With the publication of their work in the prestigious journal "Neuron"*, the team led by Haucke have succeeded in putting the processes in the right order and have ultimately settled a long-standing debate. In turn, all scientists who are concerned with the brake and the accelerator in the nervous system will benefit from these findings. Here, it is a question of diseases in which nerve cells fire electrical signals in an uncontrolled manner, because the brake mechanisms in the nervous system fail. Epilepsy is a well-known example, but an imbalance between high-frequency activity and its inhibitory counterparts also occurs in schizophrenia and autism.

FMP director Haucke does not yet see his work as providing a concrete indication of how it might be possible to therapeutically intervene in pathological processes. However, this work has laid a central foundation for further research and extended the neurosciences by an important building block of knowledge.

* "Synaptic Vesicle Endocytosis Occurs on Multiple Timescales and is Mediated by Formin-Dependent Actin Assembly" T. Soykan et al., Neuron 93, edition of 22 February 2017

Prof. Dr. Volker Haucke
Leibniz-Institut für Molekulare Pharmakologie(FMP)
Phone +49-30-94793101

Public relations
Silke Oßwald
Phone +49-30-94793104

Leibniz-Institut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
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