Researchers to explore possible approaches for designing small molecule therapeutics to combat depression.
A structural study of the brain-cell receptor GPR158, which has been linked to depression and anxiety, has uncovered the receptor’s regulating complex, enabling work on potential therapeutics designed to block GPR158 to treat depression, anxiety, and other mood disorders.
The findings, published in Science, map the atomic structure of GPR158, both on its own and when bound to a group of proteins that mediate its activity.
GPR158 has historically been difficult to study, with researchers considering it an "orphan receptor" because they have yet to identify the molecule responsible for activating its signaling function. Further, unlike most receptors in its family, GPR158 exists in close association with a protein complex called the RGS signaling complex, which acts as a brake on cellular signaling. It has been unclear why GPR158 engages it, according to the researchers.
"We've been studying this receptor for more than 10 years, and have done a lot of biology on it, so it's really gratifying to see for the first time how it's organized," said lead author Kirill Martemyanov, PhD, professor and chair of the Department of Neuroscience at the Scripps Research, in a press release.
According to the investigators, GPR158 binds RGS complex in a similar way to how other receptors engage their conventional transducers, suggesting that it employs RGS proteins as means of transducing its signal. The study also revealed the fundamental structure of the receptor is composed of 2 interconnected copies of the GPR158 proteins stabilized by phospholipids.
Finally, the investigators identified a cache domain on the side of the receptor facing outside of the cell, which they theorize serves as a trap for the molecules that activate GPR158. Cache domains have never been observed in these types of receptors before this study, according to the authors.
"I am thrilled to see the structure of this unique GPCR. It is first of its kind, showing many new features and offering a path for drug development," said first author Dipak Patil, PhD, in the release.
The researchers are now exploring possible approaches for designing small molecule therapeutics to combat depression. These include disrupting the 2-part arrangement, interfering with engagement of RGS complex, or specifically targeting the cache domain with small, drug-like molecular binders.
Chronic stress and depression boost this brain receptor; a new study maps out how to block it [news release]. Science Daily; November 18, 2021. Accessed November 23, 2021. https://www.sciencedaily.com/releases/2021/11/211118203432.htm