A common amino acid, glycine, may provide a “slow down” signal to the brain, possibly contributing to major depression, anxiety and other mood disorders in some people. This is supported by the scientists of the Wertheim UF Scripps Institute for Biomedical Innovation & Technology. The discovery, published in the magazine Science, could improve understanding of the biological causes of major depression and accelerate efforts to develop new, faster-acting drugs for such hard-to-treat mood disorders, said the neuroscientist Kirill Martemyanovauthor of the study.
“Most medications for people with depression take weeks to kick in, if at all. New and better options are really needed,” said Martemyanov, who chairs the neuroscience department at the Jupiter institute.
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Major depression is among the world‘s most pressing health care needs. The numbers have increased in recent years, especially among young adults. As depression, the number of suicides and medical costs rise, a study by the US Centers for Disease Control and Prevention in 2021 estimated the economic burden at $326 billion annually in the United States.
Martemyanov said he and his team of students spent many years working on this discovery. They have not set out to find a cause, much less a possible avenue of treatment for depression. Instead, they asked a fundamental question: ‘How do sensors on brain cells receive and transmit signals in the cells?’ Therein lies the key to understanding vision, pain, memory, behavior and perhaps much more, Martemyanov suspected.
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In 2018, Martemyanov’s team found that the new receptor was involved in stress-induced depression. If the mice didn’t have the gene for the receptor, called GPR158, they proved surprisingly resistant to chronic stress. This offered strong evidence that GPR158 could be a therapeutic target, he said.
But what sent the signal? A breakthrough came in 2021 when his team solved the structure of the GPR158. What they saw surprised them. The GPR158 receptor looked like a microscopic clamp with a compartment, similar to something they’d seen in bacteria, not human cells. “Usually receptors like GPR158, known as G protein-coupled receptors, bind to G proteins. This receptor bound to an RGS protein, which is a protein that has the opposite effect of activation,” he explained. Thibaut Labouteresearcher of Martemyanov’s group and first author of the study.
The role of cell receptors
“Scientists have been cataloging the role of cell receptors and their signaling partners for decades. Those that do not yet have known signalers, such as GPR158, have been dubbed “orphan receptors.” The discovery means that GPR158 is no longer an orphan receptor.” Laboute said.
Instead, the team renamed it mGlyR, short for ‘metabotropic glycine receptor’. “An orphaned receptor is a challenge. You want to understand how it works,” Laboute explained. “What makes me really excited about this discovery is that it could be important for people’s lives. That’s what gets me up in the morning.”
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To the wisteria
Laaboute and Martemyanov are featured as inventors in a patent application describing methods for studying the activity of GPR158. Martemyanov is a co-founder of Blueshield Therapeutics, a startup researching GPR158 developments. Glycine itself is sold as a dietary supplement classified as a mood enhancer. It is a basic building block of proteins and affects many different cell types, sometimes in complex ways.
In some cells it sends signals to slow down, while in other types of cells it sends excitatory signals. Some studies have linked glycine to the growth of invasive prostate cancer. More research is needed to understand how the body maintains the right balance of mGlyR receptors and how brain cell activity is affected, she said. She intends to keep doing it. “We are in desperate need of new treatments for depression – concluded Martemyanov -. If we can target this with something specific, it makes sense that it could help. We are working on it now”.