Researchers based at the Florida campus of The Scripps Research Institute (TSRI) say they have created detailed fingerprints of a class of surface receptors that have proven highly useful for drug development. The fingerprints show the complexity of how these receptors activate their binding partners to produce a wide range of signaling actions, according to the scientists.

The study (“Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors”), which was published in  Science Signaling, focuses on interactions of G protein-coupled receptors (GPCRs) with their signaling G protein mediators. GPCRs account for about 40% of all prescription pharmaceuticals on the market and play key roles in many physiological functions because they transmit signals from outside the cell to the interior. When an outside substance binds to a GPCR, it activates a G protein inside the cell to release components and create a specific cellular response.

“Until now, it was generally believed that GPCRs are very selective, only activating few G proteins they were designed to work with,” said Kirill Martemyanov, Ph.D., an associate professor who led the study. “It turns out the reality is much more complex.”

Ikuo Masuho, Ph.D., a senior research associate in the Martemyanov lab, added, “Our imaging technology opens a unique avenue of developing drugs that would precisely control complex GPCR-G protein coupling, maximizing therapeutic potency by activating G proteins that contribute to therapeutic efficacy while inhibiting other G proteins that cause adverse side effects.”

The study found that individual GPCRs engage multiple G proteins with varying efficacy and rates. The results depend on which G proteins bind to the receptor and for how long. The same receptor changes G protein partners, and the signaling outcome, depending on the action of the signal received from outside of the cell.

This finding was made possible by novel imaging technology used by the Martemyanov lab to monitor G protein activation in live cells. Using a pair of light-emitting proteins, one attached to the G protein, the other attached to a reporter molecule, Dr. Martemyanov and colleagues were able to measure simultaneously both the signal and activation rates of most G proteins present in the body.

“Our approach looks at 14 different types of G proteins at once, and we only have 16 in our bodies,” he said. “This is as close as it can get to what is actually happening in real time.”

Alan Smrcka, Ph.D., a professor at the University of Rochester Medical School and a prominent GPCR researcher who was not involved with the study, said he believes “this work could be very helpful for identifying previously unappreciated signaling pathways downstream of individual GPCRs that could be useful therapeutically or identified as potential side effects of GPCRs.”

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