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 big 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 understand better why some previous drugs targeting mGluRs have failed, and how future drugs could target these receptors more effectively.
