Scripps Florida Scientists Create Fingerprints for Major Drug Development Targets JUPITER, FL December 2, 2015 For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have created detailed fingerprints of a class of surface receptors that have proven highly useful for drug development.
These detailed fingerprints show the surprising complexity of how these receptors activate their binding partners to produce a wide range of signaling actions.
The study, which was published this week in the journal Science Signaling, focuses on interactions of G protein-coupled receptors (GPCRs) with their signaling mediators known as G proteins. GPCRs currently accounting for about 40 percent of all prescription pharmaceuticals on the market 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, activating only a few G proteins they were designed to work with, said TSRI Associate Professor Kirill Martemyanov, who led the study. It turns out the reality is much more complex.
Ikuo Masuho, 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, much like a dance where the most desirable partner, the GPCR, is surrounded by 14 suitors all vying for attention. The results, as in any dance, 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 what's known as a reporter molecule, Martemyanov and his 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.
In the accompanying commentary in Science Signaling, Alan Smrcka, a professor at University of Rochester Medical School and a prominent GPCR researcher, wrote, [The findings] suggest the power of the GPCR fingerprinting approach, in that it could predict the G protein coupling specificity of a GPCR in a native system, which was previously undetected by conventional analysis. This 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.
In addition to Martemyanov and Masuho, other authors of the study, Distinct Profiles of Functional Discrimination Among G Proteins Determine the Actions of G Protein Coupled Receptors, are Olga Ostrovskaya and Keqiang Xie, both of TSRI at the time of the study, and Grant M. Kramer and Christopher D. Jones of Florida Atlantic University. For the study, see http://stke.sciencemag.org/content/8/405/ra123; for the commentary, see http://stke.sciencemag.org/content/8/405/fs20
The work was supported by the National Institutes of Health (grants EY018139, DA026405, and DA036596).
About The Scripps Research Institute
The Scripps Research Institute (TSRI) is one of the worlds largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists including two Nobel laureates work toward their next discoveries. The institutes graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.
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For information:
Office of Communications
Tel: 858-784-2666
Fax: 858-784-8136
press@scripps.edu
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Scripps Florida Scientists Create Fingerprints for Major Drug Development Targets JUPITER, FL December 2, 2015 For the first time, scientists from the Florida campus of The Scripps Research Institute (TSRI) have created detailed fingerprints of a class of surface receptors that have proven highly useful for drug development.
