The treatment modalities were concluded through experiments on mice in 10 years of research

Neuroscientists have identified brain receptors associated with depression and stress, studied their structure in detail, and later demonstrated in mice that blocking this receptor reduces chronic stress and depression.

In 2018, scientists at the Scripps Research Institute in Florida, led by Grill Martimianov, discovered that brain cell receptor GPR158 was present in unusually high concentrations in the frontal cortex of people with severe depressive disorders.

They also found that mice with chronic depression had increased levels of this receptor in the cerebral cortex, and suppressing it made the animals calmer and more resilient.

“We have been studying this future for more than ten years and we have a good understanding of its biology,” says Mardimianov, a professor and chairman of the Department of Neurology at the Institute.

Historically, GPR158 has not been easy to read; Because it belongs to the group of orphan receptors, the molecules responsible for activating their signaling function have not been identified. In addition, unlike most similar receptors, it is in close contact with the RGS-signaling protein complex – the regulator of the G-protein signal – which acts as a powerful inhibitor of cellular signal.

To map the atomic structure of GPR158 to a resolution of less than a fraction of a billionth of a meter and to determine how it binds to the group of proteins that determine its function, the researchers developed a supercooled single-particle electron microscope using cryo-EM. This method relies on freezing proteins at very low temperatures and studying their structure through the lenses of powerful microscopes.

Another research author, structural biologist Dina Issart, explains: “The microscope uses beams of electrons instead of light. The wavelength of electrons, which is less than light, allows the model to be visualized with atomic resolution.

“This is the first microscope to show many new features and pave the way for drug development,” says Dr. Deepak Patel, the first author of the article, from Mardimiano’s laboratory.

Authors find additional challenge in using information about the structure of the receptor to develop low-molecular-weight agents, the treatment for depression. They are already testing a number of possible ways, including: disrupting the two-component structure of the receiver, interfering with the operation of the RGS complex, or targeting the final sections of GPR158 using molecular bonds.