To discover a new trigger mechanism for major depressive disorder, the role of glycine is critical

A new study has found that a common amino acid, glycine, sends "brake" signals to the brain, potentially affecting major depression, anxiety and other mood disorders in some people. The results of the study, titled "Orphan receptor GPR158 serves as a metabotropic glycine receptor:mGlyR," were published online March 30 in Science.

To discover a new trigger mechanism for major depressive disorder, the role of glycine is critical

Figure 1 Research results (Source: [1])

The research has contributed to a better understanding of the biological causes of major depressive disorder and could accelerate the development of new, faster-acting drugs for mood disorders that are difficult to cure. Dr. Kirill Martemyanov, a neuroscientist from the Institute for Biomedical Innovation and Technology at Scripps Research Center in Florida, is the corresponding author of the study.

Martemyanov said that the current variety of drugs for depression is limited, and if they work, most of them take several weeks. Therefore, there is an urgent need for new and better drug options. As the number of people with disabilities, suicides and medical expenses for depression has climbed in recent years, a 2021 study by the U.S. Centers for Disease Control and Prevention noted that the resulting economic burden is about $326 billion per year.

Martemyanov says he and his team's postdocs and students spent years searching for the discovery. They did not intend to look for any cause, let alone explore possible treatment options. Instead, they asked the most fundamental question: How do sensors on brain cells receive and transmit signals to the inside of the cell, which then alter the cell's activity? Martemyanov believes this could be key to understanding vision, pain, memory, behavior and other latent functions.

In 2018, Martemyanov's team discovered that the new receptor, GPR158, was involved in stress depression. If mice lacked the gene for this receptor, they showed a surprising adaptation to chronic stress. This provides strong evidence that GPR158 may be a therapeutic target. But what sends the signal?

"Basic science is evolving rapidly. Fifteen years ago, we discovered a binding partner for the protein we were interested in, which inspired us to discover this new receptor," Martemyanov said. "We're always trying to unravel the mystery."

In 2021, his team made a breakthrough in resolving the structure of GPR158. The results surprised them. The GPR158 receptor looks like a miniature clip with a compartment that resembles a structure in bacteria than in human cells.

"We got the target completely wrong before we saw the structure." Martemyanov said. "But this structure is clearly an amino acid receptor. There were only 20 amino acids, so we immediately screened and found that there was only one perfect fit, and it was glycine. ”

Notably, the signaling molecules transmitted into cells are not agonists, but inhibitors. The functional end of GPR158 is connected to a cooperative molecule that, when bound to glycine, "hit the brake" instead of "throttle."

Laboute, the first author of the study and a postdoctoral researcher in Martemyanov's group, said: "Normally, receptors like GPR158, known as G protein-coupled receptors, are connected to G proteins on the inside of the cell membrane. But GPR158 is linked to the RGS (Regulators of G protein signaling) protein. "The main role of the RGS protein is to negatively regulate the signal transduction pathway of G protein-coupled receptors. Therefore, negative negative to positive, the presence of glycine will slow down the inactivation of Gαo protein downstream of GPR158. The medial prefrontal cortex of the brain is an area closely associated with depression, where GPR158 is significantly expressed. At the same time, glycine and its transporter were also found in this area. These all hint that GPR158 could serve as a new target for antidepressant development.

To discover a new trigger mechanism for major depressive disorder, the role of glycine is critical

Figure 2: Schematic diagram of the mechanism of glycine on mGlyR (Source: [1])

The discovery meant that GPR158 was no longer an orphan receptor, and the team renamed it mGlyR, short known as the "metabolic glycine receptor."

To discover a new trigger mechanism for major depressive disorder, the role of glycine is critical

Figure 3 Schematic diagram of the interaction between glycine and GPR158 (Source: Martemyanov Laboratory of WertheimUF Scripps Institute)

"Studying how orphan recipients work is extremely challenging." Laboute said. "What excites me about this discovery is the impact it could have on people's lives. It's something that wakes me up every morning. ”

Labouse and Martemyanov are listed as inventors in a patent application describing the method for studying GPR158 activity. Martemyanov also co-founded Blueshield Therapeutics, a startup targeting GPR158.

Glycine itself is marketed as a nutritional supplement and is advertised to improve mood. It is the basic building block of proteins that produce complex roles in many different cell types. In some cells, it sends slowing signals, while in other cell types, it sends excitatory signals. Some studies have linked glycine to the growth of aggressive prostate cancer.

Martemyanov said more research is needed to understand how the body maintains the right mGlyR receptor balance and how brain cell activity is affected. "We desperately need new treatments for depression." Martemyanov said. "It might help if we can solve this problem with something specific, and that's what we're doing."

Responsible editor|Feng Lixiao

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[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


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