Major discovery about mammalian brains surprises researchers Neuroscience News

Summary: V-ATPase, a vital enzyme that enables neurotransmission, is able to turn on and off randomly, even with long breaks.

source: Copenhagen University

In a new breakthrough to understanding more about the mammalian brain, University of Copenhagen researchers have made a startling discovery. Namely, the vital enzyme that enables brain signals turns on and off at random, even taking hours-long “breaks from work.”

These findings may have a significant impact on our understanding of the brain and the development of drugs.

Today, Discovery is on the cover nature.

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

This process is essential for neural communication and the survival of all complex organisms. Until now, researchers around the world believed 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 University of Copenhagen’s Department of Chemistry closely studied the enzyme and discovered that its activity is switched on and off at random intervals, which contradicts our previous understanding.

This is the first time anyone has studied mammalian brain enzymes one molecule at a time, and we’re blown away by the result. Contrary to popular belief, and unlike many other proteins, these enzymes can be inactive for minutes to hours. However, the brains of humans and other mammals are miraculously able to function,” says Professor Demetrius Stamo, who led the study from the Center for Engineered Cellular Systems at the University of Copenhagen’s Department of Chemistry.

To date, such studies have been carried out using very stable enzymes from bacteria. Using the new method, the researchers investigated for the first time mammalian enzymes isolated from the brains of mice.

Today, the study was published in nature.

The enzymatic switch may have far-reaching implications for neural communication

Nerve cells communicate using neurotransmitters. To transmit messages between two neurons, neurotransmitters are first pumped into small membranous bladders (called synaptic vesicles). The bladder acts as a container that stores neurotransmitters and releases them between the two neurons only when it is time to deliver the message.

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

But the study shows that in each vessel there is only one enzyme. When this enzyme stops, there will be no more energy to drive the loading of neurotransmitters into the containers. This is a completely new and unexpected discovery.

“It is almost incomprehensible that the very 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 stop working,” says Professor Dimitrios Stamo.

Illustration of the envelope shows vacuolar-type adenosine triphosphatasases (V-ATPases, large blue structures) on the synaptic vesicle of a neuron in the mammalian brain. Photo: 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 interesting questions:

Does shutting down the energy supply to the containers mean that many of them are already free of neurotransmitters? Will a large portion of empty containers significantly affect communication between neurons? If so, would this be a “problem” neurons have evolved to get around, or could it be an entirely new way of encoding important information in the brain? Only time will tell.”

A revolutionary method for screening drugs for V-ATPase

The V-ATPase enzyme is an important drug target because it plays important roles in cancer, cancer metastasis, and many other life-threatening diseases. Thus, V-ATPase is a profitable target for anticancer drug development.

Current assays screening drugs for V-ATPase rely on simultaneously averaging the signal from billions of enzymes. Knowing the average effect of a drug is sufficient as long as the enzyme is working consistently at the right time or when the enzymes are working together in large numbers.

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

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

Facts about V-ATPase:

See also

This shows a diagram of the intestine and brain
  • V-ATPases are enzymes that break down ATP molecules to pump protons across cellular membranes.
  • It is found in all cells and is essential for controlling pH/acidity inside and/or outside cells.
  • In neurons, the proton gradient created by V-ATPases provides energy for the loading of neurochemical messengers called neurotransmitters into synaptic vesicles for their subsequent release into synaptic junctions.

About this research in Neuroscience News

author: press office
source: Copenhagen University
Contact: Press Office – University of Copenhagen
picture: The image is in the public domain

Original search: Closed access.
“V-ATPase regulation in the mammalian brain through ultrasonic mode switching” by Demetrius Stamo et al. nature


Regulation of V-ATPase in the mammalian brain through ultraviolet mode switching

Vacuolar-type adenosine triphosphate enzymes (V-ATPases) are electromechanical circulating enzymes structurally related to F-type ATP synthases. They hydrolyze ATP to create electrochemical proton gradients for a wide number of cellular processes.

In neurons, the loading of all neurotransmitters into synaptic vesicles is activated by about one V-ATPase molecule per synaptic vesicle. To shed light on this bona fide single-molecule biological process, we investigated electrostatic proton pumping by mammalian brain V-ATPASE bases in single synaptic vesicles.

Here we show that V-ATPases do not pump continuously in time, as suggested by observing the turnover of bacterial homologues and postulating strict ATP-proton coupling.

Instead, they randomly switched between three long-lived modes: proton pumping, inactivity, and proton leak. Remarkably, direct monitoring of pumping revealed that physiologically relevant concentrations of ATP do not regulate the rate of endogenous pumping.

ATP regulates V-ATPase activity through potential proton pump mode switching. By contrast, electrochemical gradients of protons regulate the rate of pumping and switch the pumped and inactive modes.

A direct consequence of mode switching is the random all-or-nothing fluctuations in the electrochemical gradient of synaptic vesicles that would be expected to introduce randomness in the secondary proton-driven active loading of neurotransmitters and thus may have important implications for neurotransmission.

This work reveals and underscores the mechanistic and biological importance of UV mode switching.

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