Cell: Mechanism of action of GPCRs

About a third of all drugs approved by the U.

Now, an interdisciplinary research team has gained a new understanding of how GPCRs work, taking a step toward developing improved drugs with fewer side effects

"Drugs targeting GPCRs are used to treat a wide variety of medical conditions -- heart disease, lung disease, sleep and neuropsychiatric disorders -- and GPCRs are also responsible for smell, taste, and vision," said Columbia University Vagelos College of Surgeons said Jonathan A.

But like many therapies, drugs that target GPCRs often have side effects, some of which can be serious

"In our study, we used an approach that allowed us to explore, in unprecedented detail, how drug-stimulated GPCRs activate β-arrestin, a protein that both terminates some signals and mediates others

The study, published April 27 in the journal Cell, used a cutting-edge technique called single-molecule fluorescence resonance energy transfer (smFRET) imaging

Armed with smFRET, the team decided to probe - adrenergic receptors - a prototype GPCR that is broadly relevant to many different areas of biology

By looking at the activation of β-arrestin by β-arrestin adrenergic receptors, the researchers revealed new details of how β-arrestin interacts with, and is activated by, GPCRs, both of which are required to release autoinhibition

This finding may ultimately help identify improved drugs that affect specific pathways, but not others, by modulating the binding and/or activation of β-arrestin to GPCRs

The results of this study also support the "barcode hypothesis" that different phosphorylation patterns or "barcodes" within receptors can lead to different β-arrestin activation patterns, which in turn determine downstream signaling outcomes

The scientists hope that a better understanding of the relationship between receptor "barcoding" and beta-arrestin activation can provide important insights into how specific pathways downstream, but not others, are targeted

GPCR-mediated beta-arrestin activation deconvoluted with single-molecule precision