Newly Discovered Trigger for Major Depression Opens New Possibilities for Treatments

Aug 08, 2023

Summary: Glycine, a common amino acid, appears to play a role in the development of major depression, anxiety, and other mood-related disorders.

Source: University of Florida

A common 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, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology have found.

The discovery, outlined Thursday in the journal Science, improves understanding of the biological causes of major depression and could accelerate efforts to develop new, faster-acting medications for such hard-to-treat mood disorders, said neuroscientist Kirill Martemyanov, Ph.D., corresponding author of the study.

“Most medications for people with depression take weeks before they kick in, if they do at all. New and better options are really needed,” said Martemyanov, who chairs the neuroscience department at the institute in Jupiter.

Major depression is among the world’s most urgent health needs. Its numbers have surged in recent years, especially among young adults. As depression’s disability, suicide numbers and medical expenses 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 the United States.

Martemyanov said he and his team of students and postdoctoral researchers have spent many years working toward this discovery. They didn’t set out to find a cause, much less a possible treatment route for depression. Instead, they asked a basic question: How do sensors on brain cells receive and transmit signals into the cells? Therein lay the key to understanding vision, pain, memory, behavior and possibly much more, Martemyanov suspected.

“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 said. “We’ve been unspooling this for all this time.”

In 2018 the Martemyanov team found the new receptor was involved in stress-induced depression. If mice lacked the gene for the receptor, called GPR158, they proved surprisingly resilient to chronic stress.

That offered strong evidence that GPR158 could be therapeutic target, he said. But what sent the signal?

A breakthrough came in 2021, when his team solved the structure of GPR158. What they saw surprised them. The GPR158 receptor looked like a microscopic clamp with a compartment — akin to something they had seen in bacteria, not human cells.

“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.”

That wasn’t the only odd thing. 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 Thibaut Laboute, Ph.D., a postdoctoral researcher from Martemyanov’s group and first author of the study.

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 finding means that GPR158 is no longer an orphan receptor, Laboute said. Instead, the team renamed it mGlyR, short for “metabotropic glycine receptor.”

“An orphan receptor is a challenge. You want to figure out how it works,” Laboute said. “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 are listed as inventors on a patent application describing methods to study GPR158 activity. Martemyanov is a cofounder of Blueshield Therapeutics, a startup company pursuing GPR158 as a drug target.

Glycine itself is sold as a nutritional supplement billed as improving mood. It 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.

More research is needed to understand how the body maintains the right balance of mGlyR receptors and how brain cell activity is affected, he said. He intends to keep at it.

“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.”

Funding: The research was supported by the National Institute of Health’s National Institute of Mental Health (MH105482) and National Institute of General Medical Sciences (GM069832).

Author: Eric HamiltonSource: University of FloridaContact: Eric Hamilton – University of FloridaImage: The image is in the public domain

Original Research: Closed access.“Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR” by Kirill Martemyanov et al. Science

Abstract

Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR

Glycine is a major neurotransmitter involved in several fundamental neuronal processes. The identity of the metabotropic receptor mediating slow neuromodulatory effects of glycine is unknown.

We identified an orphan G protein–coupled receptor, GPR158, as a metabotropic glycine receptor (mGlyR). Glycine and a related modulator, taurine, directly bind to a Cache domain of GPR158, and this event inhibits the activity of the intracellular signaling complex regulator of G protein signaling 7–G protein β5 (RGS7-Gβ5), which is associated with the receptor.

Glycine signals through mGlyR to inhibit production of the second messenger adenosine 3′,5′-monophosphate. We further show that glycine, but not taurine, acts through mGlyR to regulate neuronal excitability in cortical neurons.

These results identify a major neuromodulatory system involved in mediating metabotropic effects of glycine, with implications for understanding cognition and affective states.

The first paragraph of this article does not accurately represent information from the University of Florida.

“JUPITER, Fla.— A common amino acid, glycine, can deliver a “slow-down” signal to the brain, likely helping alleviate major depression, anxiety and other mood disorders in some people, scientists at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology report online in the journal Science today.”

A common 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, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology have found.

Terrible reporting.

As a basic research discovery, this is certainly an advancement of science. But the depression link is pure speculation. Glycine is not only a neurotransmitter, it is a “conditionally essential” amino acid, and a necessary building block for collagen. Messing with glycine in vivo is gonna be tricky. Perhaps scientists should first develop a coherent theory about why the depression drugs we have now sometimes work and sometimes do not. Oh and maybe science could describe exactly what serotonin has to with depression before we try to tackle glycine. Unless that is, all you care about is developing a drug that can pass FDA scrutiny.

Two things can be true in this case. There are actually a few amino acids that are “classified” as neurotransmitters; meaning that they facilitate neuronal communication through their chemical signals. Glycine has long been known to be an neurotransmitter for some time. It’s receptors were primarily known as ionotropic receptors, forming chloride channels that act to rapidly depolarize the cell membrane. This discovery in this article introduces us to a new type of glycine receptor that functions and signals differently.

“Oh and maybe science could describe exactly what serotonin has to with depression”

There’s a lot of research linking serotinergic dysfunction to major depression. It’s just scattered around in various journals and what not. Search for serotonin depression on PubMed.

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