New major depression trigger mechanism discovered, and glycine plays a crucial part!
A recent research discovered that the ubiquitous amino acid glycine can communicate "braking" signals to the brain that may have an impact on certain people's significant depression, anxiety, and other mood disorders. The study's findings, titled "Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR," were published onlinein Science on March 30.
The research advances our understanding of the biochemical underpinnings of severe depression and may hasten the creation of new, quicker-acting medications to combat this unmanageable mood disease. The study's corresponding author is Kirill Martemyanov, PhD, a neuroscientist at the Scripps Research Center in Florida's Institute for Biomedical Innovation and Technology.
In the words of Martemyanov, there is now a small selection of medications for depression, and most, if any, take several weeks to start working. Therefore, the need for new and improved medication choices is critical. According to a 2021 research by the U.S. Centers for Disease Control and Prevention, the economic burden due to the increase in the number of disabled persons, suicides, and medical expenses for depression would be roughly $326 billion year.
Martemyanov said that the quest for this finding took him and his team of postdocs and students years. They didn't set out to investigate any potential causes of the illness or potential treatments. Instead, they posed the most fundamental query: How can sensors on brain cells receive and send information, which subsequently alter the activity of the cell, within the cell?This, according to Martemyanov, may hold the key to understanding functions including vision, pain, memory, behavior, and other possible ones.
The GPR158 novel receptor was linked to stress depression in 2018, according to Martemyanov's team. If mice lacked the gene for this receptor, they displayed a startling stress adaption. This gave GPR158 considerable support as a potential target for medical treatment. But what really delivers the signal?
Science's foundations are changing quickly. We identified a binding partner for our target protein fifteen years ago, which motivated us to identify this novel receptor," said Martemyanov. We have been working to solve this puzzle.
His team cracked the code in 2021 and figured out how GPR158 was put together. The outcomes shocked them. The GPR158 receptor resembled a tiny clip with a compartment, more like a bacterial structure than a component of human cells.
"We completely missed the target until we saw the structure." stated Martemyanov. But it is obvious that the structure is an amino acid receptor. Since there are only 20 amino acids, we instantly sorted through them and discovered that only glycine matched the bill completely.
Notably, the signaling molecule sent into the cell is an inhibitor rather than an agonist, and the functional end of GPR158 is connected to a cooperative molecule that "slams on the brakes" as opposed to the "throttle" when attached to glycine.
Laboute, a postdoctoral fellow in Martemyanov's lab and the study's first author, said that a receptor like GPR158, also known as a G protein-coupled receptor, would typically be connected to a G protein on the inside of the cell membrane. However, the RGS (Regulators of G protein signaling) protein is connected to GPR158. The G protein-coupled receptor's signal transduction pathway is mostly negatively regulated by the RGS protein. Glycine would therefore delay the inactivation of G-o proteins that are downstream of GPR158. GPR158 is strongly expressed in the medial prefrontal cortex, a part of the brain that is intimately linked to depression. In this location, glycine and its transporter proteins were also discovered. These imply that GPR158 could be a potential new target for antidepressant development.
Figure 2 Schematic representation of the mechanism of glycine influence on mGlyR (Figure source: [1])
The team has given GPR158 a new moniker, mGlyR, which stands for "metabotropic glycine receptor" as a result of their research, which makes it no longer be considered an orphan receptor.
Glycine and GPR158 interaction is shown schematically in Figure 3 (Figure source: Martemyanov Laboratory, Wertheim UF Scripps Institute).
"Studying the orphan receptor's mechanism of action is incredibly difficult." stated Laboute. "The potential impact this revelation might have on people's lives is what excites me about it. Every morning, it causes me to awaken.
A patent application that describes a technique for analyzing the activity of GPR158 lists Laboute and Martemyanov as joint inventors. A startup firm called Blueshield Therapeutics, which employs GPR158 as a therapeutic target, was co-founded by Martemyanov as well.
The dietary supplement glycine itself is promoted as a mood booster. It is the fundamental component of proteins and has intricate impacts on a variety of cell types. It gives slowing signals to some cells while excitatory signals to other cell types. Glycine has been related in certain studies to the development of aggressive prostate cancer.
More study, according to Martemyanov, is required to comprehend how the body maintains the proper balance of mGlyR receptors and how this affects the activity of brain cells. "New depression treatments are desperately needed." stated Martemyanov. "If we can address this with something specific, that might help, and that's what we're working on."
References:
[1]Thibaut Laboute, Stefano Zucca, Matthew Holcomb, et al. Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR. Science, 2023; 379 (6639): 1352 DOI: 10.1126/science.add7150
[2]https://ufhealth.org/news/2023/search-major-depression-trigger-reveals-familiar-face-discovery-opens-new-possibilities
