Two studies led by Weill Cornell Medicine researchers have mapped unexpectedly varied interactions involving a receptor family that drugmakers have pursued as a target for epilepsy, depression, anxiety disorders and other brain conditions.
The findings, published Sept. 10 in Nature Communications, give researchers a more detailed view of how metabotropic glutamate receptors interact with regulatory proteins called beta arrestins. The work could help explain why some earlier drugs aimed at the receptors fell short and guide efforts to design more precise treatments, although the studies did not test a new therapy in patients.
Metabotropic glutamate receptors, or mGluRs, are found on cells throughout the body and help regulate connections between nerve cells in the brain. They belong to the large family of G protein-coupled receptors, which are involved in many cellular responses and are frequent drug targets.
Beta arrestins help control and inhibit signaling from those receptors. Scientists once viewed that regulation as relatively simple and similar across the receptor family, but recent research has shown that the physical interactions and their effects can vary considerably.
Studies catalog different receptor pairings
The Weill Cornell Medicine team used electron microscopy, molecular dynamics simulations and a new single-molecule capture method developed by the researchers. Together, those techniques revealed multiple ways mGluRs and beta arrestins can connect.
The studies showed that different mGluR subtypes can form complexes with different numbers of beta-arrestin subtypes. The proteins also connected in a range of orientations and through different molecular interactions, creating a broader set of possible complexes than researchers had previously understood.
Joshua Levitz, the studies' senior author and a professor of biochemistry and biophysics at Weill Cornell Medicine, said cataloging those possibilities is necessary before researchers can determine how to target them. He said the diversity also points to complexity in how the receptors are regulated.
Dagan Marx, a former postdoctoral researcher in Levitz's laboratory, was the first author of both studies.
High-resolution structure offers a model
The experiments focused on mGluR8, a receptor subtype involved in the brain's normal regulation of anxiety. The researchers said its structure is also broadly representative of the larger mGluR family.
A three-dimensional structure of mGluR8 provided what the team described as the first high-resolution view of an active complex formed by an mGluR and beta arrestin. Researchers can use that structure as a model for additional work on the mechanisms involved and on possible drugs.
One goal is to design drugs that affect mGluRs without increasing beta-arrestin binding. An increase in that binding could desensitize the receptors, reducing their response to a treatment. Levitz said the structures identified in the studies suggest that avoiding that response may be possible.
The studies establish a foundation for future laboratory and drug-development work rather than demonstrating that a treatment is ready for clinical use. The research was supported by the National Institutes of Health, Spain's Ministry of Universities through the Margarita Salas Fellowship, the Charles Revson Fellowship, the Rohr Family Research Scholar Award and the Monique Weill-Caulier Award.
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