Amino Acid That Delivers "Slow Down" Signal to Brain May Contribute to Major Depression

Aug 21, 2023

A model shows how glycine molecules (teal) interact with brain cell receptors called GPR158 to influence the nervous system. The dotted lines show hydrogen bonds and weak electrical field attractions that start the signal. [Courtesy of Martemyanov lab at The Wertheim UF Scripps Institute.]

The results of research headed by scientists at Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology suggest that the amino acid glycine can deliver a “slow-down” signal to the brain, likely contributing to major depression, anxiety and other mood disorders in some people.

Their in vitro study, which identified a new—previously orphan—receptor for glycine, may provide new insights into a biological cause of major depression, and could accelerate efforts to develop new, faster-acting medications for such hard-to-treat mood disorders, said neuroscientist Kirill Martemyanov, PhD, corresponding author of the team’s study in Science. “There are limited medications for people with depression,” said Martemyanov, who chairs the neuroscience department at the institute. “Most of them take weeks before they kick in, if they do at all. New and better options are really needed.”

Martemyanov and colleagues reported on their findings in a paper titled “Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR.”

Major depression is among the world’s most urgent health needs. Numbers of affected people have surged in recent years, especially among young adults. And as expenses related to the disability, suicide numbers and medical expenses associated with depression have climbed, a study by the U.S. Centers for Disease Control and Prevention in 2021 put its economic burden at $326 billion annually in U.S.

The newly published study is the result of years of work that wasn’t specifically designed to find a cause, or treatment for depression. Rather, the Martemyanov team asked the question “How do sensors on brain cells receive and transmit signals into the cells, and then change the cells’ activity?” It was in answering this question that their findings might hold the key to understanding vision, pain, memory, behavior and possibly much more.

Glycine is the simplest amino acid that is “ubiquitously present in all mammalian tissues,” the authors noted. Glycine acts as a major neurotransmitter that is involved in several fundamental processes, and can have both inhibitory and excitatory effects. “Glycine serves as an inhibitory neurotransmitter, but it can be excitatory in developing neurons.” However, the team further pointed out, “The identity of the metabotropic receptor mediating slow neuromodulatory effects of glycine is unknown. Interestingly, they commented, “Glycine has distinct effects on neural circuits, and glycinergic transmission has been implicated in pathological conditions, including depression.”

G protein coupled receptors (GPCRs) play “essential roles in neuronal physiology and pathology, and present targets for drug development,” the authors further explained. “However, many GPCRs still have no identified endogenous ligands. Orphan GPCRs may have potential for obtaining insights into physiology and for drug development.” In 2018 the Martemyanov team found a new receptor that was involved in stress-induced depression. Their studies showed that if mice lacked the gene for the receptor, called GPR158, they proved surprisingly resilient to chronic stress. “Genetic suppression of GPR158 in mice results in a prominent antidepressant phenotype and stress resiliency, making GPR158 an attractive target for development of new antidepressants,” they stated in their newly reported paper.

That offered strong evidence that GPR158 could be therapeutic target, but What sent the signal?, At this point the natural ligand for GPR158 remained unknown. A breakthrough came in 2021, when the investigators solved the structure of GPR158. What they saw surprised them. The GPR158 receptor looked like a microscopic clamp with a compartment, more akin to something they had seen in bacteria, not human cells. And what they saw led them to hypothesize that the receptor may have an amino acid ligand.

“We were barking up the completely wrong tree before we saw the structure,” Martemyanov said. “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.” The researchers then carried out a number of techniques to verify that GPR158 was a direct target of glycine.

Another unusual finding of their studies was that the signaling molecule was not an activator in the cells, but an inhibitor. The business end of GPR158 connected to a partnering molecule that hit the brakes rather than the accelerator when bound to glycine. “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,” said study first author Thibaut Laboute, PhD, a postdoctoral researcher from Martemyanov’s group.

Scientists have been cataloging the role of cell receptors and their signaling partners for decades. Those that still don’t have known signalers, such as GPR158, have been dubbed “orphan receptors.” The new findings mean that GPR158 is no longer an orphan receptor, Laboute said. Instead, the team renamed it mGlyR, short for “metabotropic glycine receptor.”

The discovery of mGlyR “opens many interesting avenues for exploring the metabotropic influence of glycine and its role in nervous system physiology,” the authors noted. “Indeed, metabotropic effects of glycine have been anecdotally noted, but molecular and circuit dissection of this influence have been limited.”

Laboute added, “An orphan receptor is a challenge. You want to figure out how it works … 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.” Martemyanov further commented, “Fifteen years ago we discovered a binding partner for proteins we were interested in, which led us to this new receptor. We’ve been unspooling this for all this time.”

Glycine itself is a basic building block of proteins and affects many different cell types, sometimes in complex ways. In some cells, it sends slow-down signals, while in other cell types, it sends excitatory signals. Some studies have linked glycine to the growth of invasive prostate cancer. Glycine is also sold as a supplement that is billed as improving mood.

More research is needed to understand how the body maintains the right balance of mGlyR receptors and how brain cell activity is affected. “We are in desperate need of new depression treatments,” Martemyanov said. “If we can target this with something specific, it makes sense that it could help. We are working on it now … It’s amazing how basic science goes.” Martemyanov said.

The authors further concluded, “we think that glycinergic signaling by means of mGlyR has implications for understanding mood disorders and for the development of new pharmacological strategies.”