Good news! Fascinating research!
"Scientists at Scripps Research, Florida have determined the near-atomic-scale structure of an unusual brain-cell receptor called GPR158, which has been linked to depression and anxiety.
The structural study reveals both the receptor and its regulating complex, advancing understanding of basic cell receptor biology. It also enables work on potential therapeutics designed to block GPR158 as a strategy for treating depression, anxiety and possibly other mood disorders.
In the study ... the researchers used ultracold, single-particle electron microscopy, or cryo-EM, to map, at a resolution of about a third of a billionth of a meter, the atomic structure of GPR158, both on its own and when bound to a group of proteins that mediate its activity.
“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,” ...
Clinical depression, also called major depressive disorder, is estimated to affect roughly 20 million people in the United States in any given year. Current treatments work on other known receptors, including monoamine, but don’t always work well for all people and alternative options are needed.
... team found in a 2018 study that GPR158 is present at unusually high levels in the prefrontal cortex of people diagnosed with major depressive disorder at the time of their death. They also found that exposing mice to chronic stress increased levels of this receptor in the mouse prefrontal cortex, leading to depression-like behavior—whereas eliminating GPR158 activity in chronically stressed mice made them resistant to depression and the effects of stress. Additionally, the activity of GPR158 receptor has been also linked to prostate cancer. ...
... team found in a 2018 study that GPR158 is present at unusually high levels in the prefrontal cortex of people diagnosed with major depressive disorder at the time of their death. They also found that exposing mice to chronic stress increased levels of this receptor in the mouse prefrontal cortex, leading to depression-like behavior—whereas eliminating GPR158 activity in chronically stressed mice made them resistant to depression and the effects of stress. Additionally, the activity of GPR158 receptor has been also linked to prostate cancer. ...
In the new study, solving the receptor’s structure offered many insights into how GPR158 works.
First, scientists found that it binds RGS complex in the same way that many receptors typically engage their conventional transducers, leading to the idea that it employs RGS proteins as means of transducing its signal.
Second, the structure revealed that the receptor exists as two interconnected copies of the GPR158 proteins stabilized by phospholipids. “These are fat-related molecules that effectively staple the two halves of the receptor together ...
First, scientists found that it binds RGS complex in the same way that many receptors typically engage their conventional transducers, leading to the idea that it employs RGS proteins as means of transducing its signal.
Second, the structure revealed that the receptor exists as two interconnected copies of the GPR158 proteins stabilized by phospholipids. “These are fat-related molecules that effectively staple the two halves of the receptor together ...
Finally, on the other side of the receptor that faces outside of the cell, an unusual module called the cache domain was revealed. The authors believe the cache domain serves as a trap for the molecules that activate GPR158. Cache domains have never been observed in these types of receptors before, demonstrating the unique biology of this orphan receptor. ..."
From the abstract:
"GPR158 is an orphan G-protein-coupled receptor (GPCR) highly expressed in the brain where it controls synapse formation and function. GPR158 has also been implicated in depression, carcinogenesis and cognition. However, the structural organization and signaling mechanisms of GPR158 are largely unknown. Here, we report structures of the human GPR158 alone and bound to an RGS signaling complex, determined using single-particle cryo-electron microscopy (cryoEM). The structures reveal a homodimeric organization stabilized by a pair of phospholipids and the presence of an extracellular Cache domain, an unusual ligand-binding domain in GPCRs.-. We further demonstrate the structural basis of GPR158 coupling to RGS7-Gβ5. Together, these results provide insights into the unusual biology of orphan receptors and the formation of GPCR-RGS complexes."
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