Inside the Secret Life of a GPCR Signaling Complex

G-protein coupled receptors (GPCRs) play a role in signaling cascades throughout the body and are targets for over one-third of all FDA-approved drugs. In a new study published in Cell, researchers describe how they were able to observe the timeline of events involved in GPCR assembly, including precisely when and how different parts of a GPCR interacts with its signaling partners. Such insights could provide vital information for target development of novel therapeutics.

The study was done by researchers from Case Western Reserve University School of Medicine. Using a technique called radiolytic footprinting that couples chemical labeling of proteins with mass analysis, they observed the formation of the GPCR signaling complex. With this technique, high intensity X-rays are used to generate highly reactive chemical labels from the water surrounding proteins, providing a snapshot of the proteins.

Historically, GPCRs have been difficult to study due to their being embedded within cell membranes. While previous studies have shown what GPCRs look like before activation and after the complexes have formed, the intermediate steps have been harder to capture. Now, the researchers were able to capture the detailed sequence of events following GPCR encounter in millisecond to minute timescales.

Using the radiolytic footprinting technique, the team was able to identify specifics of a process called the “G protein cycle” by which the GPCR transfers information to its signaling partner. In millisecond to seconds, GPCRs identify a signal (such as a hormone or drug), reconfigure themselves, recruit specific G proteins, and activate signaling cascades. Because of its ability to identify when a certain portion a GPCR locks into its target, it is able to reveal precise amino acids most central to GPCR function. This could be used to identify regions of GPCRs to target therapeutically.

In follow-up studies, the team plans to further analyze GPCR activation and combine their findings with existing GPCR structural data to get a better picture of how they work. These results could lead to development of better therapeutics including beta-blockers and chemotherapy drugs, among others.