SEP 20, 2020 5:08 AM PDT

Revealing the Structure of Hallucinogens Bound to Their Receptor

WRITTEN BY: Carmen Leitch

Recent studies have demonstrated that hallucinogenic drugs like LSD, psilocybin, and mescaline have therapeutic potential. Studies have shown that they can improve the symptoms of depression and anxiety, for example. But patients with those problems would obviously have to tolerate the significant effects of the drugs if they were to become an option for treatment. Their potential for abuse has also made them difficult to study. Researchers are working towards understanding how these drugs work on a molecule level. It may be possible to create beneficial drugs that can work therapeutically without hallucinations, or alter them so new medications can be created.

This illustration shows the chemical architecture of amino acids that make up the 5-HT2A serotonin receptor complex bound to a psychedelic compound (pink, top) Credit: Roth Lab (UNC School of Medicine)

Reporting in Cell, scientists have revealed the structure of the 5-HT2A serotonin receptor (HTR2A), a cell-surface receptor known to bind hallucinogens, while it's bound to LSD, psilocybin, and mescaline.

"Millions of people have taken these drugs recreationally, and now they are emerging as therapeutic agents," said co-senior study author Bryan L. Roth, M.D., Ph.D., the Michael Hooker Distinguished Professor of Pharmacology at the University of North Carolina School of Medicine. "Gaining this first glimpse of how they act at the molecular level is really important, a key to understanding how they work. Given the remarkable efficacy of psilocybin for depression (in Phase II trials), we are confident our findings will accelerate the discovery of fast-acting antidepressants and potentially new drugs to treat other conditions, such as severe anxiety and substance use disorder."

There are high levels of HTR2A in the cerebral cortex, and researchers have suggested that it's crucial to the effects of hallucinogens.

"When activated, the receptors cause neurons to fire in an asynchronous and disorganized fashion, putting noise into the brain's system," said Roth. "We think this is the reason these drugs cause a psychedelic experience. But it isn't at all clear how these drugs exert their therapeutic actions."

Roth's lab worked with the lab of Stanford University School of Medicine structural biologist Georgios Skiniotis, Ph.D. "A combination of several different advances allowed us to do this research," Skiniotis said. "One of these is better, more homogeneous preparations of the receptor proteins. Another is the evolution of cryo-electron microscopy technology, which allows us to view very large complexes without having to crystalize them."

Study co-first author and Skiniotis lab postdoctoral researcher Kuglae Kim, Ph.D., played an integral part in the work.

"Kuglae was amazing," Roth said. "I'm not exaggerating when I say what he accomplished is among the most difficult things to do. Over three years in a deliberate, iterative, creative process, he was able to modify the serotonin protein slightly so that we could get sufficient quantities of a stable protein to study."

This enabled the team to generate the X-ray crystallography structure of LSD bound to HTR2A for the first time. The researchers used cryo-EM to create images of a candidate hallucinogen called 25-CN-NBOH, bound to the receptor and a complex including the effector protein Gαq. This complex is involved in neurotransmitter release.

Image credit: Pixabay

"The more we understand about how these drugs bind to the receptors, the better we'll understand their signaling properties," Skiniotis said. "This work doesn't give us the whole picture yet, but it's a fairly large piece of the puzzle."

Sources: AAAS/Eurekalert! via University of North Carolina Health Care, Cell

About the Author
  • Experienced research scientist and technical expert with authorships on 28 peer-reviewed publications, traveler to over 60 countries, published photographer and internationally-exhibited painter, volunteer trained in disaster-response, CPR and DV counseling.
You May Also Like
AUG 12, 2020
Genetics & Genomics
A Switch That Lets Worms Toggle Between Sexes
AUG 12, 2020
A Switch That Lets Worms Toggle Between Sexes
People typically think of gender in binary terms, but in the natural world, there are many examples of sexual fluidity.
SEP 08, 2020
Neuroscience
Thyroid Inflammation Linked to Anxiety Disorder
SEP 08, 2020
Thyroid Inflammation Linked to Anxiety Disorder
Findings from a new study suggest that people with autoimmune inflammation in their thyroid may be more likely to develo ...
SEP 11, 2020
Cell & Molecular Biology
How Variants Affect Gene Expression Across Cell Types
SEP 11, 2020
How Variants Affect Gene Expression Across Cell Types
The Genotype-Tissue Expression (GTEx) Consortium, has produced multiple papers that have provided new insight into human ...
SEP 23, 2020
Immunology
Gene That Fuels Antibody Factories Discovered
SEP 23, 2020
Gene That Fuels Antibody Factories Discovered
Antibodies are Y-shaped proteins that play a central role in the immune system’s arsenal of germ-busting weapons. ...
OCT 09, 2020
Genetics & Genomics
Using CRISPR to Destroy Cancer Cells
OCT 09, 2020
Using CRISPR to Destroy Cancer Cells
Researchers have developed a way to selectively target certain cancer cells with CRISPR.
OCT 18, 2020
Cell & Molecular Biology
Small RNA is Connected to Bacterial Pathogenicity
OCT 18, 2020
Small RNA is Connected to Bacterial Pathogenicity
It's thought that as much as half of the global population carries a bacterium called Helicobacter pylori in their stoma ...
Loading Comments...