This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: Metabotropic glutamate receptors, which are important but difficult drug targets, interact in surprisingly varied ways with their principal regulatory proteins, according to two new studies led by Weill Cornell Medicine investigators. The findings represent a major step forward in understanding these receptors and how they can be targeted effectively to potentially treat conditions such as epilepsy, depression and anxiety disorders.
Metabotropic glutamate receptors (mGluRs) are found on cells throughout the body and are especially important as modulators of synapses in the brain. Pharmaceutical companies have long sought to target them to treat a variety of neurological and psychiatric disorders. Those efforts have fallen short of expectations, in part because mGluR activity is naturally regulated—by proteins called beta-arrestins—in ways that have not been well understood.
In the studies, published Sept. 10 in Nature Communications, the researchers established the foundation for a much better understanding of these receptors by revealing and visualizing a wide variety of mGluR-beta-arrestin interactions. The results should help researchers better understand why some previous drugs targeting mGluRs have failed and how future drugs could target these receptors more effectively. "These findings are the culmination of years of work to characterize this amazing diversity of mGluR-arrestin interactions—a diversity that suggests a lot of complexity in how these receptors are regulated and points to new opportunities for precisely targeting them with drugs," said study senior author Dr.
Joshua Levitz, a professor of biochemistry and biophysics at Weill Cornell Medicine. The first author of both studies was Dr. Dagan Marx, a former postdoctoral researcher in the Levitz laboratory.
Metabotropic glutamate receptors belong to a large class of receptors called G protein-coupled receptors (GPCRs). Researchers once believed that beta-arrestins regulate and inhibit GPCR signaling in ways that are relatively simple and similar across all members of this class. However, recent studies, including those by the Levitz laboratory, have begun to paint a more complex picture of these interactions.
In general, researchers have come to appreciate that the precise physical details of GPCR-beta-arrestin interactions and their effects on cells are still unclear for a substantial proportion of these receptors, including mGluRs. Levitz and his team used electron microscopy, molecular dynamics simulations and a new single-molecule capture method they developed to discover an unexpected variety of couplings between beta-arrestins and mGluRs. The results clarified important details for future drug design, showing, for example, how different mGluR subtypes can form complexes with different numbers of beta-arrestin subtypes in a range of orientations with different types of intermolecular interactions.
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