Targeting this special receptor in the brain relieves chronic stress and depression.

New findings from the Scripps Research Institute in Florida shed light on the anatomy of an uncommon brain cell receptor known as GPR158, which has been related to sadness and anxiety.

The structural analysis elucidates both the receptor and its regulatory complex, so increasing our understanding of fundamental cell receptor biology. Additionally, it facilitates the development of novel medicines that target GPR158 as a means of treating depression, anxiety, and maybe other mood disorders.

The study, published in the journal Science, employed ultracold, single-particle electron microscopy, or cryo-EM, to map the atomic structure of GPR158, both alone and in complex with a set of proteins that mediate its activity.

Clinical depression, often known as major depressive disorder, is estimated to afflict around 20 million people annually in the United States. Current medications target other recognized receptors, including monoamine, but they may not always work well for everyone, necessitating the development of alternate choices.

In a 2018 study, Martemyanov and colleagues discovered that GPR158 is present at exceptionally high levels in the prefrontal cortex of individuals diagnosed with major depressive illness at the time of death. Additionally, they discovered that chronic stress increased the level of this receptor in the prefrontal cortex of mice, resulting in depression-like behavior—whereas inhibiting GPR158 activity in chronically stressed animals rendered them immune to depression and stress-related consequences. Additionally, the GPR158 receptor’s activation has been associated with prostate cancer.

GPR158 has always been difficult to investigate. It is referred to as a “orphan receptor” because scientists have not yet found the molecule that activates its signaling function in a way analogous to flipping a switch. Additionally, the receptor is regarded uncommon because, unlike the majority of receptors in its family, it colocalizes with a protein complex called the RGS signaling complex in the brain. The acronym RGS stands for “regulator of G protein signaling,” and it works as a strong brake on cellular signaling. However, the reason for GPR158’s engagement has been unknown.

The current study discovered that deciphering the receptor’s structure provided numerous insights into how GPR158 functions. To begin, scientists discovered that it engages the RGS complex in the same way that many receptors generally engage their conventional transducers, implying that it transduces its signal via RGS proteins. Second, the structure revealed that the receptor is composed of two identical GPR158 proteins that are stabilized by phospholipids.

“These are fat-related molecules that effectively staple the two halves of the receptor together” explain the authors.

Finally, on the receptor’s exterior facing side, an odd module called the cache domain was discovered. According to the authors, the cache domain acts as a trap for compounds that activate GPR158. Cache domains have never been detected in these types of receptors previously, highlighting the orphan receptor’s unique biology.

According to the study authors, solving the structure provides many new insights.

“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,” the authors highlight.

The goal now is to use the structure information to inform the construction of small molecule antidepressant treatments, the study says.

The authors of the paper are currently investigating many different strategies, including interrupting the two-part arrangement, interfering with the RGS complex’s involvement, or directly targeting the cache domain with small, drug-like molecular binders. Whichever path is followed, the availability of structural knowledge should significantly aid efforts to find drugs to treat depression.

This discovery was made feasible by breakthroughs in microscopy technology, including freezing proteins at extremely low temperatures and analyzing their organization through the lens of powerful microscopes, a technique termed cryogenic electron microscopy, or Cryo-EM.

Source: 10.1126/science.abl4732

Image Credit: iStock

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