The laboratory of Brian L. Roth, MD, at the UNC School of Medicine, has paved the way for the next generation of chemogenetic tools by solving the high-resolution, complex structures of drug-like compounds that bind to receptors on designer brain cells. The study, published in the journal Nature, was led by Shichen Zhang, a postdoctoral fellow.
CHAPEL HILL, NC – Understanding how neurons regulate brain function is the first step toward developing more effective drugs to treat depression, anxiety, schizophrenia, substance abuse, epilepsy and a host of other neurological disorders.
Laboratory to manipulate and understand this fundamental feature of neurobiology Brian L. Roth, MD, Ph.DIn the mid-2000s, UNC School of Medicine Professor of Pharmacology Michael Hooker developed a chemical genetics technology called DREADD. Although the technology is widely used in neuroscience, it was unclear why the technology was so effective.
Now, etc reported in the magazine NatureThe Roth lab, led by postdoctoral researcher Shichen Zhang, used cryogenic electron microscopy to determine the detailed, high-resolution structures of four DREADDs bound to three drug-like but inactive compounds.
This work, made possible through the UNC CryoEM Core Facility, reveals key details of DREADD that should accelerate the discovery of structure-guided chemogenetic tools for the next generation.
“Although DREADD is widely used, the precise molecular basis of why it is so useful is still unknown,” Zhang said. “We think these structures will help scientists around the world, including at UNC-Chapel Hill, to explore more effective and safer treatments for many neurological diseases.”
To study how brain cells work, scientists need to target specific neural circuits — interconnected networks of cells that constantly send and receive electrical and chemical signals through receptors such as G protein-coupled receptors, which are targets for many therapies. However, this is not an easy task, which is the main reason why many drugs hit several types of receptors or activate specific receptors randomly. The results are therapeutic but have side effects.
One way to better understand neuron biology is to use chemogenetic technology. At the same time that scientists design receptor proteins that react only In pharmacologically inactive drug-like compounds called ligands that do not cause biochemical reactions in the body. Then, in experiments, the scientists implanted that receptor in a specific type of neuron. When neurons begin to express receptors, scientists add ligands to activate or inhibit the neurons.
This is how scientists can study which receptors do what and how. When Roth’s lab developed DREADD 15 years ago, scientists quickly adopted the useful technology. That’s because researchers express DREADD in specific brain cells and then use drug-like compounds to activate or inhibit cells in living animals. Since 2007, DREADD has been used by a large number of scientists around the world to identify brain cells that regulate perception, emotion, cognition, memory, sleep, and other known biological functions.
“However, we never fully understood why the drug-like compounds bind specifically to these altered designer receptors that we have created,” Roth said. “In large part, that’s because we designed receptors before their structures were elucidated.”
For that Nature in the study, Roth’s lab used cryogenic microscopy to determine the precise chemical structure of the DREADDs hM3Dq-miniGq complex (which activates neurons) and the hM4Di-miniGo complex (which inhibits neurons) associated with the drug-like drug dechloroclozapine; DREADD hM3Dq–miniGq complex binds to clozapine.N– oxide; and the DREADD hM3R–miniGq complex binds to iperoxo.
“This study provides valuable and detailed molecular insight into the mechanisms responsible for DREADD’s unique benefits,” said Roth. “These findings shed light on how these receptors, which have evolved as a result of directed evolution, are selective and efficient.”
Zhang added, “We believe this work will transform basic and translational neuroscience.”
Other authors are Ryan Gumper, X-ping Huang, Yongfeng Liu, Brian Krumm and Can Cao of the UNC School of Medicine and Jonathan Fay of the University of Maryland School of Medicine.
Media Relations: Mark DerewiczUNC School of Medicine