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. Credit: Martemyanov lab at The Wertheim UF Scripps Institute.
Key points:
- Glycine, a common amino acid, can deliver a “slow-down” signal to the brain, likely contributing to major depression.
- The discovery improves understanding of the biological causes of depression and could accelerate efforts to develop new medications.
- The University of Florida lab has been working toward this discovery for 15 years.
After nearly two decades of research, a team at the University of Florida has linked a common amino acid—glycine—to major depression, anxiety and other mood disorders, greatly improving understanding of the biological causes of depression and accelerating efforts to develop effective treatments.
“It’s amazing how basic science goes,” said neuroscientist Kirill Martemyanov, corresponding author of the study. “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.”
In 2018, Martemyanov and team discovered that the new receptor, called GPR158, was involved in stress-induced depression. If mice lacked the gene for the receptor, they proved surprisingly resilient to chronic stress. That offered strong evidence that GPR158 could be therapeutic target.
Another breakthrough came in 2021, when the researchers 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. GPR158 connects to a partnering molecule that hits the brakes rather than the accelerator when bound to glycine.
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. Instead, the team renamed it mGlyR, short for “metabotropic glycine receptor.”
Glycine itself is sold as a nutritional supplement, billed as a mood improver. 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. Additionally, some studies have linked glycine to the growth of invasive prostate cancer.
The team says they will keep researching to understand how the body maintains the right balance of mGlyR receptors and how brain cell activity is affected.
Information from UF Health.