New target receptor for treating depression GPR158

Researchers from the Scripps Research Institute find a new target receptor called GPR158 for treating depression. Their research shows that individuals with high levels of above receptor may be more susceptible to depression following chronic stress.

“The next step in this process is to come up with a drug that can target this receptor,” says Kirill Martemyanov, Ph.D., co-chair of the TSRI Department of Neuroscience and senior author of the new study, which is published in the journal eLife.

“We need to know what is happening in the brain so that we can develop more efficient therapies,” says Cesare Orlandi, Ph.D., the senior research associate at TSRI and co-first author of the study.

The researchers found elevated GPR158 protein in depressed patients, suspected it could play a major role in the disease process. They then conducted an animal study using male and female mice with and without above receptor. Subsequent behavioral tests showed that mice with elevated levels of GPR158 showed signs of depression following chronic stress and suppressing GPR158 protected them from developing depressive behavior and also resilient to stress.

Next, the researchers examined why GPR158 has these effects on depression. The team demonstrated that GPR158 affects key signaling pathways involved in mood regulation in the region of the brain called prefrontal cortex, though the researchers emphasized that the exact mechanisms remain to be established.

Martemyanov explains that GPR158 is a so-called “orphan receptor” (which gets its name because its binding partner/partners are unknown) with a poorly understood biology and mechanism of action. GPR158 appears to work downstream from other important brain systems, such as the GABA, a major player in the brain’s inhibitory control and adrenergic system involved in stress effects.

Laurie Sutton, Ph.D., a research associate at TSRI and co-first author of the study, says this finding matches what doctors have noticed in people who have experienced chronic stress. “There’s always a small population that is resilient they don’t show the depressive phenotype,” says Sutton.

As the search goes on for additional targets for depression, Martemyanov says scientists are increasingly using new tools in genome analysis to identify orphan receptors like GPR158. “Those are the untapped biology of our genomes, with significant potential for development of innovative therapeutics,” he says.

Citation: Sutton, Laurie P., Cesare Orlandi, Chenghui Song, Won Chan Oh, Brian S. Muntean, Keqiang Xie, Alice Filippini, Xiangyang Xie, Rachel Satterfield, Jazmine D W Yaeger, Kenneth J. Renner, Samuel M. Young, Baoji Xu, Hyungbae Kwon, and Kirill A. Martemyanov. “Orphan receptor GPR158 controls stress-induced depression.” ELife 7 (2018). doi:10.7554/elife.33273.

Research funding: National Institutes of Health, University of Iowa, Max Planck Society, Canadian Institutes of Health Research Fellowship.

Adapted from press release by the Scripps Research Institute.