Scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology have identified a newly discovered trigger that could contribute to major depression, anxiety, and other mood disorders in some people.
The amino acid glycine has been shown to stimulate the production of serotonin, a hormone that is associated with positive emotions and is often referred to as the “feel-good” chemical. Serotonin can help to improve mood, enhance memory and thinking, and promote better sleep.
In studies on rodents, researchers found that glycine supplementation led to increased serotonin levels. As a result of these findings, some individuals consider glycine supplements to be a “natural antidepressant” for treating depression.
Researchers at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology have discovered that a common amino acid called glycine can send a “slow-down” signal to the brain, which could potentially contribute to the development of major depression, anxiety, and other mood disorders in certain individuals.
The study, which was published in the journal Science today, sheds new light on the biological causes of major depression and could pave the way for the development of faster-acting medications to treat these difficult mood disorders.
According to the study’s corresponding author, neuroscientist Kirill Martemyanov, Ph.D., this discovery has opened up new possibilities for treatment.
“Most medications for people with depression take weeks before they kick in, if they do at all. New and better options are really needed,” remarks Martemyanov.
One of the most pressing health needs in the world today is major depression, which has seen a significant increase in numbers, particularly among young adults. This has resulted in a rise in disability, suicide rates, and medical expenses, with a 2021 study by the U.S. Centers for Disease Control and Prevention estimating the annual economic burden of major depression in the United States at $326 billion.
Neuroscientist Kirill Martemyanov, Ph.D., and his team of students and postdoctoral researchers have spent several years on their discovery, which was not initially aimed at finding the cause or a possible treatment for depression. Rather, they were focused on understanding how sensors on brain cells receive and transmit signals into the cells, which could provide insights into a range of functions such as vision, pain, memory, and behavior.
“It’s amazing how basic science goes. Fifteen years ago we discovered a binding partner for proteins we were interested in, which led us to this new receptor,” Martemyanov adds. “We’ve been unspooling this for all this time.”
Back in 2018, the team led by Martemyanov discovered that a new receptor, GPR158, was linked to stress-induced depression. They found that mice that lacked this receptor gene showed a remarkable resilience to chronic stress, providing compelling evidence that GPR158 could be a potential therapeutic target. However, the question remained: what triggers the receptor?
The breakthrough came in 2021 when Martemyanov’s team was able to solve the structure of GPR158. To their surprise, they found that the GPR158 receptor resembled a tiny clamp with a compartment, similar to what they had previously seen in bacteria rather than human cells.
“We were barking up the completely wrong tree before we saw the structure,” Martemyanov comments. “We said, ‘Wow, that’s an amino acid receptor. There are only 20, so we screened them right away and only one fit perfectly. That was it. It was glycine.”
In addition to the unexpected structure of GPR158, there was another surprising finding: the signaling molecule associated with it acted as an inhibitor rather than an activator in cells. The crucial part of GPR158 interacted with a complementary molecule that slowed down rather than sped up when glycine bound to it.
“Usually receptors like GPR158, known as G protein Coupled Receptors, bind G proteins. This receptor was binding an RGS protein, which is a protein that has the opposite effect of activation,” adds first author Thibaut Laboute.
For many years, scientists have been documenting the functions of cell receptors and their associated signaling partners. Some receptors, like GPR158, which did not have known signalers, were referred to as “orphan receptors.”
However, the discovery of the connection between GPR158 and glycine means that it is no longer an orphan receptor, according to Laboute. Instead, the team has renamed it mGlyR, which stands for “metabotropic glycine receptor.”
“An orphan receptor is a challenge. You want to figure out how it works,” Laboute adds. “What makes me really excited about this discovery is that it may be important for people’s lives. That’s what gets me up in the morning.”
Laboute and Martemyanov have filed a patent application that outlines methods for studying GPR158 activity. Furthermore, Martemyanov has also founded Blueshield Therapeutics, a startup that is exploring GPR158 as a potential drug target.
Although glycine is sold as a nutritional supplement that claims to enhance mood, it is a fundamental protein-building block that affects various cell types in diverse and sometimes intricate ways. While glycine can send slow-down signals in certain cells, it can also send excitatory signals in others. Some research has even associated glycine with the growth of invasive prostate cancer.
Martemyanov acknowledges that further research is required to comprehend how the body regulates the correct balance of mGlyR receptors and how it affects brain cell activity. Nonetheless, he is committed to continuing his investigations in this field.
“We are in desperate need of new depression treatments,” Martemyanov adds. “If we can target this with something specific, it makes sense that it could help. We are working on it now.”
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