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This brain receptor is boosted by chronic stress and sadness; a new research shows how to stop it

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Scientists have revealed the structure of GPR158, a component linked to serious depression, providing a much-needed new treatment option for those suffering from mood disorders.

GPR158 activity was knocked down in stressed mice, making them resistant to sadness and anxiety. The nature of the peculiar brain receptor is revealed in a new research published in the journal Science, as well as potential techniques to minimize its influence with medicine.

The structure of an uncommon brain-cell receptor termed GPR158, which has been related to depression and anxiety, has been established at the near-atomic size by scientists at Scripps Research in Florida. The structural analysis shows the receptor as well as its regulatory complex, enhancing our knowledge of fundamental cell receptor biology. It also allows researchers to explore on new therapies that target GPR158 as a treatment for depression, anxiety, and maybe other mood disorders.

The researchers used ultracold, single-particle electron microscopy, or cryo-EM, to map the atomic structure of GPR158, both on its own and when bound to a group of proteins that mediate its activity, at a resolution of about a third of a billionth of a meter, in the study, which was published Nov. 18 in the journal Science.

“We’ve been researching this receptor for over a decade and have done a lot of biology on it,” says lead scientist Kirill Martemyanov, PhD, Professor and Chair of the Department of Neuroscience at Scripps Research.

Clinical depression, often known as major depressive disorder, affects about 20 million individuals in the United States each year. Current medicines target other recognized receptors, including monoamine, but they don’t always work for everyone, necessitating the development of new medications.

GPR158 is present at abnormally high levels in the prefrontal cortex of persons diagnosed with severe depressive illness at the time of death, according to Martemyanov and his colleagues in a 2018 research. They also discovered that chronic stress raised levels of this receptor in the mouse prefrontal cortex, resulting in depression-like behavior, but inhibiting GPR158 activity in chronically stressed mice rendered them resistant to depression and stress-related consequences. The activation of the GPR158 receptor has also been associated to prostate cancer.

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GPR158 hasn’t always been straightforward to research. It’s dubbed a “orphan receptor” because scientists haven’t yet discovered the molecule that turns its signaling function “on” in the same way that a switch does. The receptor is especially noteworthy because, unlike other receptors in its family, it coexists in the brain with a protein complex known as the RGS signaling complex. RGS stands for “regulator of G protein signaling” and serves as a potent signaling brake. However, it is unknown why GPR158 activates it.

The structure of the receptor was solved in the recent research, which revealed a lot about how GPR158 operates. First, scientists discovered that it contacts RGS complex in the same manner as many receptors do with their traditional transducers, implying that it uses RGS proteins to transmit its signal. Second, the structure showed that the receptor is made up of two linked GPR158 proteins that are held together by phospholipids.

Martemyanov notes, “These are fat-related chemicals that essentially staple the two parts of the receptor together.”

Finally, an uncommon module known as the cache domain was discovered on the exterior of the cell side of the receptor. The cache domain, according to the scientists, acts as a trap for the chemicals that activate GPR158. Cache domains have never been seen previously in these sorts of receptors, showing the orphan receptor’s unique biochemistry.

The structure’s solution, according to first author Dipak Patil, PhD, a staff scientist at the Martemyanov laboratory, presents several new insights.

“I’m ecstatic to observe the structure of this one-of-a-kind GPCR. It’s the first of its type, with a slew of new features and a roadmap for drug development “Patil explains.

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Martemyanov says that the goal now is to utilize the knowledge gathered from the structure to influence the development of small molecule therapies to treat depression.

He’s currently looking at interrupting the two-part arrangement, interfering with RGS complex involvement, and particularly targeting the cache domain with tiny, drug-like molecular binders, to name a few possibilities. Regardless matter the path selected, Martemyanov believes that having structural knowledge available would considerably aid medication development attempts to treat depression.

The newest technical developments in microscopy enabled this investigation, which included freezing proteins at ultra-low temperatures and studying their arrangement through the lens of powerful microscopes, a process known as cryogenic electron microscopy, or Cryo-EM.

“To view protein assemblies, the microscope employs an electron beam rather than light. We were able to view our sample at near-atomic precision because electrons have a shorter wavelength than light “Professor Tina Izard, PhD, a structural biologist, agrees. The work was co-authored by Patrick Griffin, PhD, Scripps Research, Florida scientific director, who used a structural proteomic platform technology.

“The potential for Cryo-EM to achieve substantial advancements in biomolecular structure resolution is huge. Our Institute is dedicated to growing Cryo-EM microscopy, which has been made feasible by the recent purchase and installation of a new microscope on campus.”

Researchers from Columbia University and Appu Singh, PhD, a structural biologist at the Indian Institute of Technology in Kanpur, collaborated on the project.

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