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A major discovery about the mammalian brain surprises researchers

A major discovery about the mammalian brain surprises researchers

A major discovery about the mammalian brain surprises researchers

Summary: V-ATPase, a vital enzyme that enables neurotransmission, can be turned on and off randomly, even with breaks of hours.

Source: University of Copenhagen

In a new breakthrough to better understand the mammalian brain, researchers from the University of Copenhagen have made an incredible discovery. Namely, the vital enzyme that enables brain signals is randomly switched on and off, even with several hours of “breaks from work”.

These discoveries could have a major impact on our understanding of the brain and the development of pharmaceuticals.

Today, this discovery is on the front page Nature.

Millions of neurons are constantly sending messages to each other to form thoughts and memories and allow us to move our bodies at will. When two neurons meet to exchange a message, neurotransmitters are transferred from one neuron to the other with the help of a unique enzyme.

This process is crucial for neuronal communication and the survival of all complex organisms. Until now, researchers around the world thought that these enzymes were active at all times to continuously transmit essential signals. But this is far from the case.

Using an innovative method, researchers from the Department of Chemistry at the University of Copenhagen closely studied the enzyme and found that its activity switches on and off at random intervals, which contradicts our previous understanding.

“This is the first time anyone has studied these mammalian brain enzymes one molecule at a time, and we are amazed by the result. Contrary to popular belief, and unlike many other proteins, these enzymes can stop working for minutes to hours. Yet the brains of humans and other mammals are miraculously capable of functioning,” says Professor Dimitrios Stamou, who led the study from the Center for Geometrically Engineered Cell Systems at the Department of Chemistry at the University of Copenhagen.

So far, such studies have been carried out with very stable enzymes from bacteria. Using the new method, the researchers investigated mammalian enzymes isolated from rat brains for the first time.

Today, the study was published in Nature.

Enzyme switching can have far-reaching implications for neuronal communication

Neurons communicate using neurotransmitters. To transmit messages between two neurons, neurotransmitters are first pumped into small membrane vesicles (called synaptic vesicles). Vesicles act as containers that store neurotransmitters and release them between two neurons only when it’s time to deliver a message.

The central enzyme of this study, known as V-ATPase, is responsible for supplying energy to the neurotransmitter pumps in these containers. Without it, neurotransmitters would not be pumped into the containers, and the containers would not be able to transmit messages between neurons.

But the study shows that there is only one enzyme in each container; when this enzyme is turned off, there would be no energy left to drive the loading of neurotransmitters into the containers. This is a completely new and unexpected discovery.

“It is almost incomprehensible that the extremely critical process of loading neurotransmitters into containers is delegated to only one molecule per container. Especially when we find that 40% of the time these molecules are turned off,” says Professor Dimitrios Stamou.

The cover illustration shows vacuolar-type adenosine triphosphatases (V-ATPases, large blue structures) on a synaptic vesicle from nerve cells in the mammalian brain. Image: C. Kutzner, H. Grubmüller and R. Jahn/Max Planck Institute for Multidisciplinary Sciences. Credit: C. Kutzner, H. Grubmüller and R. Jahn/Max Planck Institute for Multidisciplinary Sciences.

These findings raise many intriguing questions:

“Does sealing energy sources in containers mean that many of them are really empty of neurotransmitters? Would a large proportion of empty containers significantly affect communication between neurons? If so, would this be a ‘problem’ that neurons evolved to work around, or could it be an entirely new way of encoding important information in the brain? Only time will tell,” he says.

A revolutionary method for screening drugs for V-ATPase

The enzyme V-ATPase is an important drug target because it plays a critical role in cancer, cancer metastasis, and several other life-threatening diseases. Therefore, V-ATPase is a lucrative target for anticancer drug development.

Existing V-ATPase drug screening assays are based on the simultaneous averaging of signals from billions of enzymes. Knowing the average effect of the drug is sufficient as long as the enzyme acts consistently over time or when the enzymes work together in large numbers.

“However, we now know that neither is necessarily true for V-ATPase. As a result, it suddenly became critical to have methods that measure the behavior of individual V-ATPases in order to understand and optimize the desired effect of a drug,” says first author Dr. Elefterios Kosmidis, Department of Chemistry. , University of Copenhagen, who led the experiments in the laboratory.

The method developed here is the first ever to measure the effects of drugs on the proton pumping of single V-ATPase molecules. It can detect currents more than a million times smaller than the gold standard method.

Facts about the enzyme V-ATPase:

See also

A major discovery about the mammalian brain surprises researchers
  • V-ATPases are enzymes that break down ATP molecules to pump protons across cell membranes.
  • They are found in all cells and are necessary to control the pH/acidity inside and/or outside the cells.
  • In neuronal cells, the proton gradient established by V-ATPases provides the energy to load neurochemical messengers called neurotransmitters into synaptic vesicles for subsequent release at synaptic junctions.

About this news about neuroscience research

Author: Press Office
Source: University of Copenhagen
Contact: Press Office – University of Copenhagen
picture: Image is in the public domain

Original Research: Closed access.
Regulation of mammalian brain V-ATPase through ultraslow mode switching” Dimitrios Stamou et al. Nature


Abstract

Regulation of mammalian brain V-ATPase through ultraslow mode switching

Vacuolar-type adenosine triphosphatases (V-ATPases) are electrogenic rotary mechanoenzymes structurally related to F-type ATP synthases. They hydrolyze ATP to establish electrochemical proton gradients for a multitude of cellular processes.

In neurons, the loading of all neurotransmitters into synaptic vesicles is facilitated by about one molecule of V-ATPase per synaptic vesicle. To shed light on this plausible single-molecule biological process, we investigated the electrogenic proton pump by individual mammalian brain V-ATPases in single synaptic vesicles.

Here we show that V-ATPases do not pump continuously in time, as suggested by the observation of rotation of bacterial homologs and the assumption of strict ATP-proton coupling.

Instead, they switch stochastically between three ultralong-lived modes: proton pump, inactive, and proton leak. In particular, direct observation of pumping revealed that physiologically relevant concentrations of ATP do not regulate intrinsic pumping rate.

ATP regulates V-ATPase activity through the ability to switch the proton pumping mode. In contrast, electrochemical proton gradients regulate the pumping rate and the switching of pumping and inactive modes.

A direct consequence of mode switching are stochastic all-or-none fluctuations in the electrochemical gradient of synaptic vesicles that would be expected to introduce stochasticity into proton-driven secondary active neurotransmitter loading and thus may have important implications for neurotransmission.

This work reveals and highlights the mechanistic and biological importance of ultraslow mode switching.



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