Structure of depression-linked brain receptor solved, offering possible new treatment route Powerful microscopic view of factor involved in major depression and chronic stress offers insights into cell signaling, presenting a possible way to tackle mood disorders.
November 18, 2021
JUPITER, FL 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, published Nov. 18 in the journal Science, 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, says lead author Kirill Martemyanov, PhD, Professor and Chair of the Department of Neuroscience at the Scripps Research.
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.
Martemyanov and his 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.
Historically, GPR158 hasn't been easy to study. It is called an orphan receptor because scientists haven't yet identified the molecule responsible for turning its signaling function on in a manner similar to flipping a switch. The receptor is also considered unusual because, in the brain, unlike most receptors in its family, it exists in close association with a protein complex called the RGS signaling complex. RGS is short for regulator of G protein signaling and it acts as a powerful brake on cellular signaling. However, it has been unclear why GPR158 engages it.
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 Martemyanov explains.
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.
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 challenge is now to use the information gleaned from the structure to inform the design of small molecule therapeutics to combat depression, Martemyanov adds.
He is now exploring several possible approaches, including disrupting the two-part arrangement, interfering with engagement of RGS complex, or by specifically targeting the cache domain with small, drug-like molecular binders. Regardless of the road taken, availability of structural information should greatly facilitate drug development efforts to treat depression, Martemyanov says.
This study was made possible by the latest technological advances in microscopy, including freezing proteins at ultra-cold temperatures and examining their organization through the lens of powerful microscopes, a technique called cryogenic electron microscopy, or Cryo-EM.
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.
Patrick Griffin, PhD, Scripps Research, Florida scientific director, co-authored the study, applying a structural proteomic platform technology.
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.
The study was a collaboration including researchers from Columbia University and Appu Singh, PhD, a structural biologist at the Indian Institute of Technology in Kanpur.
In addition to professors Martemyanov, Griffin, Izard and Singh, and Staff Scientist Patil, the authors of the study, Cryo-E
Most recent headlines
09/11/2025
Dalet today announced a transformative leap forward for media operations: Agentic Artificial Intelligence (AI) that unifies the Dalet ecosystem under one natura...
16/10/2025
The XR Sports Alliance (XRSA) has announced the third cohort of members. The new members include MLSE, Vegas Golden Knights, Pro Climbing League, FansXR, Focal ...
16/10/2025
NEW YORK The Broadcasters Foundation of America has launched its 2025 Year-End Giving Campaign which seeks to raise donations from tax-deductible personal and c...
16/10/2025
NEW YORK Australias Nine Network and the National Hockey League (NHL) today announced a media partnership that will bring the worlds premier professional ice ho...
16/10/2025
Parks Associates has released new data showing that nearly half (45%) of U.S. internet homes watch free ad-supported streaming TV (FAST) services and 89% of U.S...
16/10/2025
TROY, Mich. -New data from J.D. Power's 2025 U.S. Residential Internet Service Provider Study shows that residential wireless internet providers are growing...
16/10/2025
This Saturday October 18 Katja Mia will burst onto the radio airwaves for the first time as she joins 2FM. Katja will be standing in for Bl thnaid Treacy on Sat...
16/10/2025
This October, RT is delighted to support Wexford Festival Opera, Babor International Arts Festival for Children, Open House Dublin and 36 other arts and cultu...
16/10/2025
GeForce NOW is more than just a platform to stream fresh games every week - it offers celebrations for the gamers who make it epic, with member rewards to sweet...
15/10/2025
Across the world, early-career reporters are interrogating systems that shape daily life, from mortuaries and classrooms to the corridors of legal education and...
15/10/2025
St. Louis Blues Pay Tribute to Ozzy Osbourne in New Pregame Open VideoThe NHL franchise worked with production firms 2WEI and 4th Floor CreativeBy Mark J Burns,...
15/10/2025
Cobalt Digital, G3DVu, Proxima Vision, and Telos Alliance Renew Premier Sponsors...
15/10/2025
By Paige Bethmann
Before my grandmother passed away in 2019, I went to visit her in the hospital where she'd been for a few weeks. When I arrived, the nurs...
15/10/2025
Two years ago, Spotify set out to grow the entire publishing industry by making ...
15/10/2025
People turn to DJ for a listening experience that feels personal, dynamic, and j...
15/10/2025
Las personas recurren a DJ para vivir una experiencia de escucha personal, din m...
15/10/2025
Rock legend Bruce Springsteen and luminary actor Jeremy Allen White came togethe...
15/10/2025
At Spotify, we're all about supporting rising talent and helping them connec...
15/10/2025
New SBS Documentary Series THE CANCER KILLERS Premieres 4 November on SBS & SBS ...
15/10/2025
SBS celebrates the Festivals of Lights with bold, illuminating stories across th...
15/10/2025
One of humanity's most profound questions continues: Is there any place in our galaxy suitable for life beyond Earth? NASA intends to find out, with the hel...
15/10/2025
eds3_5_jq(document).ready(function($) { $(#eds_sliderM519).chameleonSlider_2_1({ content_source:......
15/10/2025
Scality, a global leader in cyber-resilient storage software for the AI era, today announced the advancement of its comprehensive AI ecosystem certification pro...
15/10/2025
The Hollywood Professional Association (HPA) today unveiled key highlights of the 2026 HPA Tech Retreat, scheduled for Feb. 15 19 at the Westin Rancho Mirage Go...
15/10/2025
At NAB Show New York 2025 (Stand 244), Interra Systems will showcase the future of media QC, monitoring, and captioning, highlighting its award-winning, AI- and...
15/10/2025
Grass Valley today announced that RMC BFM, part of the CMA-CGM Group and France's third-largest private media group, has chosen Grass Valley's productio...
15/10/2025
Appear, the global leader in live production technology, will demonstrate how its powerful hardware and software innovations are shaping the future of hybrid, s...
15/10/2025
Rakim to Join Berklee's Hip-Hop Hall of Fame at Signature Series Concert The rap icon becomes the latest inductee, following luminaries such as Roxanne Sh...
15/10/2025
Berklee Brings Live Music to the Head of the Charles Student artists will perform on multiple riverfront stages during the 60th anniversary of the world's...
15/10/2025
CobbTV, the government access television channel for Cobb County, Ga. recently acquired an automated playout system from Pebble, a global provider of automation...
15/10/2025
OSLO, Norway Appear, the global leader in live production technology, will demonstrate how its powerful hardware and software innovations are shaping the future...
15/10/2025
NEW YORK The NBA is making major changes to the NBA App and NBA TV as it takes control of them from TNT Sports, which has long managed the league's digital ...
15/10/2025
SAN MATEO, Calif. In what promises to be a major expansion of interactive features and personalized content on the DirecTV platform, the operator and Glance hav...
15/10/2025
SAN JOSE, Calif. Roku has launched changes to its user interface (UI) that the streaming platform says will better showcase original programming on the platform...
15/10/2025
LOS ANGELES Software-defined data storage and data services provider OpenDrives has elevated Alex Dunfey to chief technology officer, responsible for driving th...
15/10/2025
Abu Dhabi, UAE October 15, 2025: Space42 (ADX: SPACE42), the UAE-based AI-powe...
15/10/2025
Sheldon Nichols and Will Trickett to find and prepare more classic cars for budget conscious would-be owners from Wiser Films
UKTV have recommissioned the clas...
15/10/2025
Wednesday 15 October 2025
Nick Cave
JPEG (275 KB)
Explore the creative univer...
15/10/2025
Wednesday 15 October 2025
From breaking up with your partner to quitting your job - new polling shows some messages are just too scary to send
Over a fifth (...
15/10/2025
Rohde & Schwarz unveils compact MXO 3 oscilloscopes with 4 and 8 channels: Advan...
15/10/2025
Back to All News
Revenge Series The Resurrected' Captivates Audiences Across Asia
Entertainment
15 October 2025
GlobalTaiwan
Link copied to clipboard
...
15/10/2025
Back to All News
Bringing the Best in VFX and Virtual Production Together as Eyeline
Jeffrey Shapiro
CEO, Eyeline
Business
15 October 2025
GlobalCanadaInd...
15/10/2025
Deployed by Astound Business Solutions, Harmonic's Primary Distribution Solution Ensures Outstanding Video Quality and Seamless Ad Insertion at the Edge
SA...
15/10/2025
Collaboration extends a trusted relationship as RMC BFM invests in scalable, fut...
15/10/2025
Series coming in 2026 stars Tom Vaughan-Lawlor, Justine Mitchell and Jason O'Mara released today
RT today released first look images of new comedy-drama ...
14/10/2025
SVG Europe Summit 2025: All Sessions Now Available to Watch on SVG PLAYNetworking event that preceded IBC2025 shone a light on elite live sports innovation acro...
14/10/2025
SVG Sit-Down: Author Rich Podolsky on Writing Madden & Summerall: How They Revo...
14/10/2025
SVG All-Stars: Michael Reiners, Coordinating Producer, FloRacingThe Illinois State grad steers a vast schedule of motorsports events at tracks across the countr...
14/10/2025
Content protection: Getting the right management for your DRM By Neal Romanek
Friday, October 10, 2025 - 10:11
Print This Story
Eluvio power the EPCR'...
Structure of depression-linked brain receptor solved, offering possible new treatment route Powerful microscopic view of factor involved in major depression and chronic stress offers insights into cell signaling, presenting a possible way to tackle mood disorders.
