Scientists elucidate how DREADD technology highjacks neuronal activity

Understanding of how neuronal activity modulates brain function is a key first step towards creating more effective drugs to treat a variety of neuropsychiatric illnesses, including depression, anxiety, schizophrenia, substance abuse, epilepsy, and others.

To both manipulate and understand this basic feature of neuronal biology, the lab of Bryan L. Roth, MD, PhD, the Michael Hooker Distinguished Professor of Pharmacology at the UNC School of Medicine, created a chemogenetic technology called DREADD — designer receptors exclusively activated by designer drugs — in the mid-2000s. Even though this technology is used ubiquitously in the neurosciences, why the technology was so efficient was unknown.

Now, as reported in the journal Nature, the Roth lab led by postdoctoral researcher Shicheng Zhang, PhD, used cryogenic electron microscopy to determine the detailed, high resolution structures of four DREADDs bound to three drug-like but inert compounds.

This work, made possible through the UNC CryoEM Core Facility, reveals key details of DREADDs that should accelerate the structure-guided discovery of next-generation chemogenetic tools.

“Although DREADDs are widely used, the precise molecular basis for why they are so useful has been obscure until now,” Zhang said. “We think these structures will help scientists around the world, including here at UNC-Chapel Hill, investigate the development of more effective and safer therapeutics for a host of neuropsychiatric conditions.”

To study how brain cells function, scientists need to target specific neural circuits — a network of interconnected cells that constantly send and receive electrical and chemical signals through receptors, such as G protein-coupled receptors, which are the intended targets of many therapeutics. This, though, is no easy task, which is the main reason why many drugs strike several kinds of receptors or activate specific receptors in unintended ways. The result might be a beneficial therapeutic effect, but also side effects.

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