Newly discovered trigger for major depression opens new possibilities for treatments

Sly Saint · Apr 27, 2023

Date:
March 30, 2023
Source:
University of Florida
Summary:
The simple amino acid glycine looks to be a previously unknown contributor to depression.

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."
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rest of article here
Newly discovered trigger for major depression opens new possibilities for treatments -- ScienceDaily

research paper
Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR

A metabotropic glycine receptor
Until now, ion channels were the only receptors known to mediate the inhibitory effects of glycine. However, glycine can also exert modulatory metabotropic effects through as-yet unclear mechanisms. Laboute et al. discovered that the orphan receptor GPR158 acts as a metabotropic glycine receptor. In analogy to the well-known metabotropic glutamate receptors (mGluRs), they named it mGlyR. This new receptor is a member of the G protein–coupled receptor family, which signals by altering the concentration of the central second messenger cyclic adenosine monophosphate. Glycine is directly recognized by a ligand-binding Cache domain present in mGlyR and regulates the activity of cortical neurons. This work introduces an additional neuromodulatory component that will give further insights into synaptic transmission. —PRS
Abstract
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.
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paywalled
Orphan receptor GPR158 serves as a metabotropic glycine receptor: mGlyR | Science

Creekside · Apr 27, 2023

More confirmation on how little is known about how the body works. ME could involve some similar still-undiscovered mechanism, possibly involving highly localized (won't show on blood or CSF tests) concentrations among only a few cells in the brain.

Okay, that thought alone is a trigger for major depression.

Wonko · Apr 27, 2023

Lots of science, lots of work, all to avoid doing anything to change the system which might make life less depressing for the masses.

It's not our fault, it's not the systems fault, it's this little amino acids fault.

boolybooly · Apr 27, 2023

Glycine is a ubiquitous AA in food and is considered by many a mood enhancer !? It is not likely to be causing depression.

This mechanism probably evolved to function as a food consumption related behavioural deactivation feedback loop which makes well fed people relax or even switch to non foraging related behaviours, like socialising etc.

If you suppress this feedback loop pharmacologically, I would bet people will eat more, become more neurotic and less able to relax and sleep properly, maybe even less sociable.

I dont think chronically stressed mice represents a valid model for depression either.

The molecular mechanism may be real but associating it with depression is IMHO unjustified. However depression is where the money is... some people will say anything to get a research grant.

Solstice · Apr 28, 2023

Wonko said: ↑

Lots of science, lots of work, all to avoid doing anything to change the system which might make life less depressing for the masses.

It's not our fault, it's not the systems fault, it's this little amino acids fault.
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Why shouldn't we do both? Sure the way society is set up can make one depressed, I see my nieces and nephews go to schools that are increasingly akin to workplaces and they loathe the experience. This vacation time is the first I've seen them truly happy for weeks. But if there are defects in our body or in our brains that can cause depression we should find those out too and try to cure it. How can finding out more about our bodies be a negative?

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Newly discovered trigger for major depression opens new possibilities for treatments

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