Cryo-EM Reveals Brain-Cell Receptor Linked to Depression and Anxiety in Near-Atomic-Scale

Researchers at Scripps Research, Florida, Columbia University, and the Indian Institute of Technology in Kanpur report by using cryo-EM, they have observed the near-atomic-scale structure of a brain-cell receptor called GPR158 that is linked to depression and anxiety. Their findings may lead to new approaches and therapeutics for treating depression, anxiety, and other mood disorders.

Their findings are published in the journal Science in a paper titled “Cryo-EM structure of human GPR158 receptor coupled to the RGS7-Gβ5 signaling complex.”

“GPR158 is an orphan G-protein-coupled receptor (GPCR) highly expressed in the brain where it controls synapse formation and function,” write the researchers. “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).”

Cryo-EM cartoon rendition of the structure of a brain receptor linked to depression, shown with its signaling complex. The assembly is called GPR158-RGS7-G5. The GPR158 protomers are shown in green and raspberry colors, RGS7 in blue and G5 in orange. The lipid bilayer is gray. Image courtesy of Martemyanov lab, Scripps Research Florida.[Martemyanov lab, Scripps Research Florida]

“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,” explains lead author Kirill Martemyanov, PhD, professor and Chair of the Department of Neuroscience at the Scripps Research.

Martemyanov and his team previously found that GPR158 was present at high levels in the prefrontal cortex of people diagnosed with major depressive disorder at the time of their death.

In the new study, the researchers found “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.”

First author Dipak Patil, PhD, a staff scientist in the Martemyanov laboratory, says 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,” Patil says.

“The microscope uses a beam of electrons instead of light to image protein assemblies. The shorter wavelength of electrons compared to light allowed us to visualize our sample at near-atomic resolution,” says structural biologist Professor Tina Izard, PhD.

“The promise of Cryo-EM for achieving significant breakthroughs in solving structures of biomolecules is enormous. Our Institute is firmly committed to expanding Cryo-EM microscopy, which is made possible through the recent acquisition and installation of a new microscope on campus.”